Crush resistant delayed-release dosage forms

ABSTRACT

The invention relates to a dosage form comprising a physiologically effective amount of a physiologically active substance (A), a synthetic, semi-synthetic or natural polymer (C), optionally one or more physiologically acceptable auxiliary substances (B) and optionally a synthetic, semi-synthetic or natural wax (D), wherein the dosage form exhibits a resistance to crushing of at least 400 N and wherein under physiological conditions the release of the physiologically active substances (A) from the dosage form is at least partially delayed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from German Patent Application No. 102005 005 446.3, filed on Feb. 4, 2005 and U.S. patent application Ser.No. 10/718,112 filed on Nov. 20, 2003.

BACKGROUND OF THE INVENTION

The present invention relates to a dosage form for administering aphysiologically active substance (A), wherein the dosage form ismechanically stabilised, such that it cannot be comminuted byconventional methods, such as pounding, crushing, grinding in a mortaretc., or at least comminuted only with very great difficulty. Thesubstance (A) is released from the dosage form according to theinvention under physiological conditions with an at least partiallydelayed release profile.

Numerous physiologically active substances, such as nutritionalsupplements, pharmaceutical substances etc., are provided asdelayed-release formulations, i.e., in contrast to conventionalformulations (for example “immediate release” formulations), release ofthe substances from these formulations into the body is delayed for acomparatively long period, which often amounts to several hours. Releaseof the substance from the dosage form, on the one hand, andmetabolisation or excretion by the organism; on the other hand, ensure arelatively uniform blood plasma level for the administered substance. Asa consequence thereof, the number of dosage units which need to be takenper day by patients can frequently be reduced, intake often beingrequired only once or twice a day.

In certain cases, delayed-release formulations may also reduce theextent of side-effects caused by the substance. Thus, for example, somepharmaceutical substances produce intensified side-effects if a givenlimit concentration of the pharmaceutical substance in the blood plasmais exceeded at least transiently. Such pharmaceutical substances aretherefore generally unsuitable for “immediate release” formulations, inparticular if it is desired to administer said formulations only two orthree times daily. Such pharmaceutical substances are thereforeconventionally administered as delayed-release formulations, wherebycontinuous release of the active ingredient is ensured and short-termoccurrence of elevated concentrations is prevented.

In delayed-release formulations, the physiologically active substance isconventionally either embedded in a matrix controlling release and/orthe dosage form is coated with a film which controls release.

However, older patients in particular frequently have difficulties intaking solid dosage forms, such as tablets, gelatine capsules, etc. Theychoke on them and sometimes develop pronounced aversion to such dosageforms.

To counter this problem, various apparatuses have been developed bymeans of which solid dosage forms may be comminuted or pulverised(“tablet crushers”). Such apparatuses are used, for example, by the carestaff in old people's homes. The dosage forms are then administered tothe people being cared for not as tablets etc. but rather as powder, forexample to get round the difficulties involved in swallowing tablets.

However, the comminution of dosage forms with such apparatuses isproblematic if the dosage forms are delayed-release formulations. As arule, comminution then results in destruction of the inner structure ofthe dosage form, which is responsible for the delayed release, so doingaway with the delayed-release action. As a result of comminution, thediffusion paths of the physiologically active substances containedtherein are shortened and/or the diffusion barriers are removed. Forinstance, a delayed-release formulation in which delayed release isachieved by means of a film coating exhibits the film coating over onlya small percentage of its solid surface after comminution. Consequently,after administration, frequently all the physiologically activesubstance originally contained in the dosage form is released in arelatively short time, whereby a comparatively very high plasmaconcentration of the substance is abruptly reached for a relativelyshort period. In this way, the original delayed-release formulationsbecome “immediate release” formulations.

Depending on the physiological activity of the substance, this may causeconsiderable side-effects however, and in extreme cases may even lead tothe death of the patient. Examples of substances with such a hazardpotential are antiparkinson drugs, antiepileptics, antidiabetics,antihypertensives, antiarrhythmics, etc.

As a rule, the people who comminute the dosage forms for themselves orfor others are not aware of these risks. Cases are known in whichpatients have died probably as a result of pulverisation ofdelayed-release formulations by nurses or carers. For further details,reference may be made for example to J. E. Mitchell, Oral Dosage FormsThat Should Not Be Crushed: 2000 Update, Hospital Pharmacy, 2000; H.Miller et al., To Crush or Not to Crush, Nursing 2000; R. Griffith etal., Tablet Crushing and the law: the implications for nursing; Prof.Nurse 2003; J. G. Schier et al, Fatality from administration oflabetalol and crushed extended-release nifedipine, Ann. Pharmacotherapy2003; A. James, The legal and clinical implications of crushing tabletmedication, Nurse Times 2005, 100(50), 28-9; and P. Cornish, “Avoid theCrush”: hazards of medication administration in patients with dysphagiaor a feeding tube, CMAJ. 2005, 172(7), 871-2.

Delayed-release formulations may also cause problems for small children.For instance, children frequently cannot distinguish solid dosage formsfrom sweets. If children find such dosage forms, for example becausetheir parents have carelessly left them lying around in the home, thereis a risk that the children may think that the dosage forms are sweetsand put them in their mouths and chew them. If said dosage forms aredelayed-release formulations, which contain a pharmaceutical substancein a dosage intended for adults, the child may in such a case already beat risk of overdose due to the relatively large amount of pharmaceuticalsubstance contained therein. By chewing the dosage form and thuscancelling out the delayed-release action, this risk is increased stillfurther, however, since the excessively high dose already containedtherein is additionally released over a greatly reduced period of time,a situation which would be very hazardous even for an adult and whichmay have all the more drastic consequences for a child.

The chewing of delayed-release formulations may also lead to an overdoseof the substance contained therein in adults. Sometimes adults chew thedosage forms deliberately, though often in ignorance of the type andpurpose of a delayed-release formulation, because they hope for aquicker effect.

A known way of reducing the risks involved in comminutingdelayed-release formulations consists in adding to the dosage formantagonists, i.e. antidotes, or compounds which produce defensivereactions, wherein the physiological action of these additives are asfar as possible manifested only if the dosage form has been comminutedprior to administration. This method has the disadvantage, however, thatthe physiologically active substance is nonetheless administered innon-delayed form and that the organism is additionally exposed to afurther physiologically active substance, for example an antidote, or toa defensive reaction, such as for example vomiting.

There is a need for pharmaceutical dosage forms with delayed releasewhich reduce the risk of overdose, such that e.g. antidotes etc. may bedispensed with.

Thus, it is an object of the invention to provide a dosage form havingadvantages over the dosage forms of the prior art. The dosage formshould release a physiologically active substance on a delayed-releasebasis but should reduce the risk of overdose, in particular as aconsequence of improper handling of the dosage form, such as chewing,crushing, grinding in a mortar etc.

SUMMARY OF THE INVENTION

It has surprisingly been found that this object is achieved by a dosageform comprising

a physiologically effective amount of a physiologically active substance(A) (=component (A));

optionally one or more physiologically acceptable auxiliary substances(B) (=component (B));

a synthetic, semi-synthetic or natural polymer (C) (=component (C)); and

optionally a physiologically acceptable synthetic, semi-synthetic ornatural wax (=component (D));

wherein the dosage form exhibits a resistance to crushing of at least400 N, and in increasingly preferred embodiments of at least 420 N, atleast 440 N, at least 460 N, at least 480 N or of at least 500 N, andwherein under physiological conditions the release of thephysiologically active substance (A) from the dosage form is at leastpartially delayed.

The dosage form according to the invention exhibits mechanical strengthover a wide temperature range, in addition to the resistance to crushingoptionally also sufficient hardness and impact strength for it to bevirtually impossible to comminute or pulverise by chewing, grinding in amortar, pounding, etc., even by means of commercially availableapparatuses for pulverising conventional dosage forms. This is notnecessarily achieved by the hardness of the dosage form. For instance,the impact strength of the dosage form according to the invention andits resistance to crushing, respectively, may in particular also meanthat it may be deformed as a result of external mechanical action, forexample using a hammer, but does not crumble into a number of fragments.Comminution is not even successful when the dosage form is initiallychilled to increase its brittleness, for example to temperatures below−25° C., below −40° C. or indeed in liquid nitrogen.

As a consequence of the resistance to crushing, delayed release ismaintained and an overdose due to improper handling of the dosage formis effectively prevented.

The advantageous properties of the dosage form according to theinvention, in particular also its mechanical properties, may notautomatically be achieved by simply processing components (A), (C),optionally (B) and optionally (D) by means of conventional methods forthe preparation of dosage forms. In fact, usually suitable apparatusesmust be selected for the preparation and critical processing parametersmust be adjusted, particularly pressure/force, temperature and time.Only if in the course of the preparation of the dosage form thecomponents are exposed to a sufficient pressure at a sufficienttemperature for a sufficient period of time, dosage forms exhibiting thedesired properties may be obtained. Thus, even if conventionalapparatuses are used, the process protocols usually must be adapted inorder to meet the required criteria.

Delayed release is understood according to the invention preferably tomean a release profile in which the physiologically active substance isreleased over a relatively long period with reduced intake frequencywith the purpose of extended therapeutic action. This is achieved inparticular with peroral administration. The expression “with at leastpartially delayed release” covers according to the invention any dosageforms which ensure modified release of the physiologically activesubstances contained therein. The dosage forms preferably comprisecoated or uncoated dosage forms, which are produced with specificauxiliary substances, by particular processes or by a combination of thetwo possible options in order purposefully to change the release rate orlocation of release.

In the case of the dosage forms according to the invention, the releasetime profile may be modified e.g. as follows: extended release, repeataction release, prolonged release and sustained release.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an ultrasound device used to supply energy for productionof the dosage form.

FIG. 2 shows a section through a planetary gear extruder.

FIG. 3 shows the mode of operation of the planetary gear extruder.

FIG. 4 shows a schematic view of the extrudate of the composition.

FIGS. 5A and 5B show schematic views of the preferred arrangements ofthe tubular domain within the dosage form.

FIG. 6 shows the measurement of the crush resistance of a tablet.

FIG. 7 shows a probe for measurement of the crush resistance.

DETAILED DESCRIPTION OF THE INVENTION

For the purpose of the specification “extended release” means a productin which the release of active substance is delayed for a finite lagtime, after which release is unhindered.

For the purpose of the specification “repeat action release” means aproduct in which a first portion of active substance is releasedinitially, followed by at least one further portion of active substancebeing released subsequently.

For the purpose of the specification “prolonged release” means a productin which the rate of release of active substance from the formulationafter administration has been reduced, in order to maintain therapeuticactivity, to reduce toxic effects, or for some other therapeuticpurpose.

For the purpose of the specification “sustained release” means a way offormulating a medicine so that it is released into the body steadily,over a long period of time, thus reducing the dosing frequency. Forfurther details, reference may be made, for example, to K. H. Bauer,Lehrbuch der Pharmazeutischen Technologie, 6th edition, W V G Stuttgart,1999; and European Pharmacopoeia.

In increasingly preferred embodiments, after 5 hours under physiologicalconditions, the dosage form has released not more than 99%, or not morethan 90%, or not more than 75%, or not more than 50%, or not more than40% or not more than 30% of substance (A). It is particularly preferablefor the dosage form in this case to contain neither tramadolhydrochloride, nor oxycodone hydrochloride, or more desirably, no opioid[N02A] (for the meaning of “N02A” see below). Release is determinedusing the standardised method in the European Pharmacopoeia, preferablyunder the conditions stated in Example 1.

In a preferred embodiment, under physiological conditions the dosageform according to the invention has released after 30 minutes 0.1 to75%, after 240 minutes 0.5 to 95%, after 480 minutes 1.0 to 100% andafter 720 minutes 2.5 to 100% of substance (A).

Further embodiments exhibit release profiles 1 to 5 and are summarisedin the table here below [all data in wt.-% of released component (A)]:time [h] No. 1 No. 2 No. 3 No. 4 No. 5 1  0-30 0-50  0-50 15-25 20-50 2 0-40 0-75  0-75 25-35 40-75 4  3-55 3-95 10-95 30-45 60-95 8 10-6510-100  35-100 40-60  80-100 12 20-75 20-100  55-100 55-70  90-100 1630-88 30-100  70-100 60-75 24  50-100 50-100 >90 36 >80 >80

The release properties of the dosage form according to the invention aresubstantially independent from the pH value of the release medium, i.e.preferably the release profile in artificial intestinal juicesubstantially corresponds to the release profile in artificial gastricjuice. At any given time point the release profiles deviate from oneanother by not more than 20%, in increasingly preferred embodiments, thedeviation is not more than 15%, or not more than 10%, or not more than7.5%, or not more than 5.0% or not more than 2.5%.

Preferably, the dosage form according to the invention exhibits anuniform release profile. Preferably, the release profile of thephysiologically active substance (A) is interindividually uniform (i.e.when comparing dosage forms obtained from the same process) and/oruniform within a single dosage form (i.e. when comparing segments of thesame dosage form). Desirably, when comparing two probes each having amass of preferably 500 mg, the total amount of the released activesubstance for any given time point of the measurement does not deviateby more than 20%, or not more than 15%, or not more than 10%, or notmore than 7.5%, or not more than 5.0% or not more than 2.5%.

The release profile of the dosage form according to the presentinvention is stable upon storage, such as upon storage at elevatedtemperature, e.g. 37° C., for 3 months in sealed containers. In thisregard “stable” means that when comparing the initial release profilewith the release profile after storage, at any given time point therelease profiles deviate from one another by not more than 20%, or notmore than 15%, or not more than 10%, or not more than 7.5%, or not morethan 5.0% or not more than 2.5%, with the later being most preferred.

By using certain polymers in suitable quantities and under suitableconditions, a resistance to crushing is achieved according to theinvention for the dosage form of at least 400 N, or of at least 420 N,or of at least 440 N, or of at least 460 N, or of at least 480 N or ofat least 500 N (measured as stated in the description; the preferredmethod for measuring the resistance to crushing according to theinvention is a modification of the method disclosed in the EuropeanPharmacopoeia 5.0, page 235, 2.9.8 “Resistance to Crushing of Tablets”).It is thereby possible effectively to prevent comminution, for examplepulverisation, of the dosage form using conventional means.

For the purpose of the specification, “comminution” means pulverisationof the dosage form by the application of force with conventional means,such as for example a pestle and mortar, a hammer, a mallet or otherusual means for pulverisation, in particular devices developed for thispurpose (tablet crushers), wherein the proportion of fines which mayarise (particle size equal to or smaller than 0.3 mm) must not exceed 5wt. %.

The dosage form according to the invention is therefore suitable forpreventing overdosing on physiologically active substances, inparticular nutritional supplements and pharmaceutical substances, whichare provided in delayed-release formulations. It is then possible todispense with antidotes, irritants etc. In addition to preventingoverdoses and the accompanying risks for patients, the dosage formsaccording to the invention additionally ensure that the other advantagesof delayed-release formulation, such as for example uniform release overa relatively long period, are retained and cannot easily be overcome.

To achieve the necessary resistance to crushing of the dosage formaccording to the invention, at least one synthetic, semi-synthetic ornatural polymer (C) is used, which contributes considerably to theelevated resistance to crushing of the dosage form. The resistance tocrushing of the dosage form amounts to at least 400 N, to at least 420N, to at least 440 N, to at least 460 N or to at least 480 N, whereinthe resistance to crushing is determined using the method stated in thedescription. In a preferred embodiment, the resistance to crushing ofthe dosage form amounts to at least 500 N, to at least 600 N, to atleast 700 N, to at least 800 N, to at least 900 N, to at least 1000 N oreven to at least 1100 N.

Besides its resistance to crushing, the dosage form according to theinvention is preferably featured by further mechanical properties, e.g.its hardness, impact resistance, impact elasticity and/or modulus ofelasticity, optionally also at low temperatures (e.g. below −24° C.,below −40° C. or in liquid nitrogen).

In increasingly preferred embodiments, the dosage form according to theinvention has a density of at least 0.80 or at least 0.85 g/cm³, atleast 0.90 or at least 0.95 g/cm³, at least 1.00, at least 1.05 or atleast 1.10 g/cm³, in the range from 0.80 to 1.35 g/cm³, and inparticular in the range from 0.95 to 1.25 g/cm³.

The dosage form according to the invention is characterized by acomparatively homogeneous distribution of density. Preferably, thedensities of two segments of the dosage form having a volume of 1.0 mm³each, deviate from one another by not more than ±10%, or by not morethan more than +7.5%, or by not more than ±5.0%, or by not more than±2.5%, and in particular by not more than ±1.0%.

The dosage form according to the invention is characterized by acomparatively homogeneous distribution of the physiologically activesubstance (A). Preferably, the content of component (A) in two segmentsof the dosage form having a volume of 1.0 mm³ each, deviates from oneanother by not more than ±10%, more preferably not more than more than±7.5%, still more preferably not more than ±5.0%, most preferably notmore than ±2.5%, and in particular not more than ±1.0%.

Preferably, the total weight of the dosage form according to theinvention is within the range from 0.01 g to 1.5 g, more preferably 0.05g to 1.2 g, still more preferably 0.1 g to 1.0 g, most preferably 0.2 gto 0.9 g and in particular 0.25 g to 0.8 g.

The dosage form according to the invention preferably contains at leastone synthetic, semi-synthetic or natural polymer (C). For the purpose ofthe specification a “semi-synthetic” product has been produced bychemical manipulation of naturally occurring substances.

Particularly preferred are high molecular weight polymers with apreferably weight average molecular weight (M_(w)) or viscosity averagemolecular weight (M_(□)) of at least 0.5·10⁶ g/mol, of at least 1.0·10⁶g/mol, of at least 2.5·10⁶ g/mol, of at least 5.0·10⁶ g/mol, of at least7.5·10⁶ g/mol or of at least 10·10⁶ g/mol, preferably 1.0·10⁶ g/mol to15·10⁶ g/mol. Suitable methods for determining M_(w) or M_(□) are knownto the person skilled in the art. Preferably, M_(□) is determined usingrheological measurements and M_(w) is determined using gel permeationchromatography (GPC) on suitable phases.

The polymers (C) preferably have a viscosity at 25° C. of 4,500 to17,600 cP, measured in a 5 wt. % aqueous solution using a model RVFBrookfield viscosimeter (spindle no. 2/rotational speed 2 rpm), of 400to 4,000 cP, measured on a 2 wt. % aqueous solution using the statedviscosimeter (spindle no. 1 or 3/rotational speed 10 rpm) or of 1,650 to10,000 cP, measured on a 1 wt. % aqueous solution using the statedviscosimeter (spindle no. 2/rotational speed 2 rpm).

Individual or combinations of polymers may be selected from the groupcomprising polyalkylene oxide, preferably polymethylene oxide,polyethylene oxide, polypropylene oxide; polyethylene, polypropylene,polyvinyl chloride, polycarbonate, polystyrene, polyacrylate,poly(hydroxy fatty acids), such as for examplepoly(3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol®),poly(hydroxyvaleric acid); polycaprolactone, polyvinyl alcohol,polyesteramide, polyethylene succinate, polylactone, polyglycolide,polyurethane, polyvinylpyrrolidone, polyamide, polylactide, polyacetal(for example polysaccharides optionally with modified side chains),polylactide/glycolide, polylactone, polyglycolide, polyorthoester,polyanhydride, block polymers of polyethylene glycol and polybutyleneterephthalate (Polyactive®), polyanhydride (Polifeprosan), copolymersthereof, block-copolymers thereof, and mixtures of at least two of thestated polymers, or other polymers with the above characteristics.

Thermoplastic polyalkylene oxides having a weight average molecularweight (M_(w)) or a viscosity average molecular weight (M_(□)) of atleast 0.5·10⁶ g/mol are particularly preferred, e.g. polyethyleneoxides, polypropylene oxides or the (block-)copolymers thereof.

In a preferred embodiment according to the invention component (C)comprises

a polyalkylene oxide having a weight average molecular weight (M_(w)) orviscosity average molecular weight (M_(□)) of at least 0.5·10⁶ g/mol

in combination with at least one further polymer, preferably also havinga weight average molecular weight (M_(w)) or viscosity average molecularweight (M_(□)) of at least 0.5·10⁶ g/mol, selected from the groupconsisting of polyethylene, polypropylene, polyvinyl chloride,polycarbonate, polystyrene, polyacrylate, poly(hydroxy fatty acids),polycaprolactone, polyvinyl alcohol, polyesteramide, polyethylenesuccinate, polylactone, polyglycolide, polyurethane,polyvinylpyrrolidone, polyamide, polylactide, polyacetal,polylactide/glycolide, polylactone, polyglycolide, polyorthoester,polyanhydride, block polymers of polyethylene glycol and polybutyleneterephthalate, polyanhydride and copolymers thereof.

Preferably, the content of said further polymer amounts to 1.0 to 25wt.-%, more preferably 5.0 to 10 wt.-%, based on the total weight ofpolymer (C).

The polymer (C) is preferably used in the form of powder. It may bewater-soluble.

In one embodiment, the polymer (C) is used in a quantity of at least 20wt. %, preferably at least 30 wt. %, more preferably at least 40 wt. %,most preferably at least 50 wt. % and in particular at least 60 wt. %,relative to the total weight of the dosage form. In a preferredembodiment it is used in a quantity of from about 20 to about 49 wt.-%,relative to the total weight of the dosage form.

The dosage form according to the invention is suitable for theadministration of a number of physiologically active substances (A) in asingle dosage form. Preferably, the dosage form contains only oneparticular physiologically active substance (A), preferably anutritional supplement or a pharmaceutical substance (=pharmaceuticalactive ingredient).

The amount of the physiologically active substance (A), based on thetotal amount of the dosage form, is preferably within the range from0.01 to 95 wt.-%, more preferably from 0.5 to 80 wt.-%, still morepreferably 1.0 to 70 wt.-%, most preferably 5.0 to 60 wt.-% and inparticular 10 to 50 wt.-%. In a preferred embodiment it is more than 20wt.-%.

In a preferred embodiment the dosage form according to the inventiondoes not contain a psychotropically acting substance as thephysiologically active substance (A). The person skilled in the artknows which substances have a psychotropic action. Substances whichinfluence psychological processes commonly have a psychotropic action,i.e. they act specifically on psychological functions. Substances with apsychotropic action may thus influence mood, either raising or loweringit. For the purpose of the description, substances with a psychotropicaction include in particular opioids, stimulants, tranquillisers (e.g.barbiturates and benzodiazepines) and other narcotics. Substances with apsychotropic action preferably comprise substances which, in particularwhen improperly administered (in particular with the intention ofabuse), cause an accelerated increase in active ingredient levelsrelative to proper oral administration, giving the abuser the desiredeffect, namely the “kick” or “rush”. This kick is also obtained if thepowdered dosage form is administered nasally, i.e. is sniffed.Substances with a psychotropic action are preferably substances which(in the appropriate dose and dosage form and when administeredappropriately) influence human mental activity and/or sensory perceptionin such a way that they are fundamentally suited to abuse.

The following opiates, opioids, tranquillisers or other narcotics aresubstances with a psychotropic action, i.e. have a potential of abuse,and hence are preferably not contained in the dosage form according tothe invention: alfentanil, allobarbital, allylprodine, alphaprodine,alprazolam, amfepramone, amphetamine, amphetaminil, amobarbital,anileridine, apocodeine, barbital, bemidone, benzylmorphine,bezitramide, bromazepam, brotizolam, buprenorphine, butobarbital,butorphanol, camazepam, carfentanil, cathine/D-norpseudoephedrine,chlordiazepoxide, clobazam clofedanol, clonazepam, clonitazene,clorazepate, clotiazepam, cloxazolam, cocaine, codeine, cyclobarbital,cyclorphan, cyprenorphine, delorazepam, desomorphine, dextromoramide,dextropropoxyphene, dezocine, diampromide, diamorphone, diazepam,dihydrocodeine, dihydromorphine, dihydromorphone, dimenoxadol,dimephetamol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone,dronabinol, eptazocine, estazolam, ethoheptazine,ethylmethylthiambutene, ethyl loflazepate, ethylmorphine, etonitazene,etorphine, fencamfamine, fenethylline, fenpipramide, fenproporex,fentanyl, fludiazepam, flunitrazepam, flurazepam, halazepam,haloxazolam, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, hydroxymethylmorphinan, ketazolam, ketobemidone,levacetylmethadol (LAAM), levomethadone, levorphanol,levophenacylmorphane, levoxemacin, lofentanil, loprazolam, lorazepam,lormetazepam, mazindol, medazepam, mefenorex, meperidine, meprobamate,metapon, meptazinol, metazocine, methylmorphine, metamphetamine,methadone, methaqualone, 3-methylfentanyl, 4-methylfentanyl,methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam,modafinil, morphine, myrophine, nabilone, nalbuphene, nalorphine,narceine, nicomorphine, nimetazepam, nitrazepam, nordazepam,norlevorphanol, normethadone, normorphine, norpipanone, opium, oxazepam,oxazolam, oxycodone, oxymorphone, Papaver somniferum, papaveretum,pernoline, pentazocine, pentobarbital, pethidine, phenadoxone,phenomorphane, phenazocine, phenoperidine, piminodine, pholcodeine,phenmetrazine, phenobarbital, phentermine, pinazepam, pipradrol,piritramide, prazepam, profadol, proheptazine, promedol, properidine,propoxyphene, remifentanil, secbutabarbital, secobarbital, sufentanil,temazepam, tetrazepam, tilidine (cis and trans), tramadol, triazolam,vinylbital, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide,(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol,(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,preferably as racemate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(6-methoxy-naphthalen-2-yl)propionate,(RR-SS)-2-acetoxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-4-chloro-2-hydroxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-5-nitro-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, andcorresponding stereoisomeric compounds, in each case the correspondingderivatives thereof, physiologically acceptable enantiomers,stereoisomers, diastereomers and racemates and the physiologicallyacceptable derivatives thereof, e.g. ethers, esters or amides, and ineach case the physiologically acceptable compounds thereof, inparticular the salts thereof and solvates, e.g. hydrochlorides.

In particular, the dosage form according to the invention preferablydoes not contain a psychotropically acting substance selected from thegroup consisting of opioids [A07DA, N01AH, N02A, R05DA, R05FA,];barbiturates [N01AF, N01AG, N03AA]; benzodiazepine derivatives [N03AE];agents for treating opiate dependency [N07BC]; anxiolytics [N05B];hypnotics and sedatives [N05C]; psychostimulants, agents for treatingattention-deficit/hyperactivity disorder (ADHD) and nootropics [N06B];antiemetics [A04A]; antiobesity preparations excluding diet products[A08A]; centrally acting muscle relaxants [M03B]; and antidotes [V03AB].The abbreviations stated in square brackets here correspond to the ATCIndex, as used by the WHO for classifying pharmaceutical substances(preferred version: January 2005 or 2006). Further details regarding theATC Index may, for example, be found in U. Fricke, J. Günther,Anatomisch-therapeutisch-chemische Klassifikation mit Tagesdosen für dendeutschen Arzneimittelmarkt: Methodik der ATC-Klassifikation undDDD-Festlegung [Anatomical therapeutic chemical classification withdaily doses for the German pharmaceuticals market: methodology of ATCclassification and DDD assignment]. ATC index with DDDs,Wissenschaftliches Institut der AOK; and Swiss Pharmaceutical Society,Index Nominum: International Drug Directory, CRC Press; 18th edition(Jan. 31, 2004).

In a preferred embodiment the dosage form according to the inventiondoes not contain a compounds selected from the group consisting of

analgesics such as aspirin, acetaminophen, deflunisal and the like;

anesthetics such as lidocaine, procaine, benzocaine, xylocalne and thelike;

antiarthritics and anti-inflammatory agents such as phenylbutazone,indomethacin, sulindac, dexamethasone, ibuprofen, allopurinol,oxyphenbutazone probenecid, cortisone, hydrocortisone, betamethasone,dexamethasone, fluocortolone, prednisolone, triamcinolone, indomethacin,sulindac and its salts and corresponding sulfide and the like;

antiasthma drugs such as theophylline, ephedrine, beclomethasonedipropionate, epinephrine and the like;

urinary tract disinfectives such as sulfarmethoxazole, trimethoprim,nitrofurantoin, norfloxicin, and the like;

anticoagulants such as heparin, bishydroxy coumarin, warfarin and thelike;

anticonvulsants such as diphenylhydantoin, diazepam and the like;

antidepressants such as amitriptyline, chlordiazepoxide, perphenazine,protriptyline, imipramine, doxepin and the like;

agents useful in the treatment of diabetics and regulation of bloodsugar, such as insulin, tolbutamide, tolazamide, somatotropin,acetohexamide, chlorpropamide and the like;

antineoplastics such as adriamycin, fluouracil, methotrexate,asparaginase and the like;

antipsychotics such as prochlorperazine, lithium carbonate, lithiumcitrate, thioridazine, molindone, fluphenazine, trifluoperazine,perphenazine, amitriptyline, triflupromazine and the like;

antihypertensives such as spironolactone, methyldopa, hydralazine,clonidine, chlorothiazide, deserpidine, timolol, propanolol, metaprotol,prazosin hydrochloride, reserpine and the like;

muscle relaxants such as mephalan, danbrolene, cyclobenzaprine,methocarbarnol, diazepam, succinoyl chloride and the like;

antiprotozoals such as chloramphenicol, chloroquine, trimethoprim andsulfamethoxazole;

spermicidals such as nonoxynol;

antibacterial substances such as beta-lactam antibiotics, tetracyclines,chloramphenicol, neomycin, cefoxitin, thienamycin, gramicidin,bacitracin, sulfonamides, aminoglycoside antibiotics, tobramycin,nitrofurazone, nalidixic acid und analogs and the antimicrobialcombination of fludalanine/pentizidone;

antihistamines and decongestants such as perilamine, chlorpheniramine(e.g. chlorpheniramine maleate), tetrahydrozoline und antazoline;

antiparasitic compounds such as ivermectin;

antiviral compounds such as acyclovir and interferon;

antifungal, amoebicidal, trichomonacidal agents or antiprotozoals suchas polyoxyethylene nonylphenol, alkylaryl sulfonate, oxyquinolinesulfate, miconazole nitrate, sulfanil amide, candicidin, sulfisoxazole,nysatidin, clotrimazole, metronidazol and the like; and

losoxanthrone, theophylline or □-hydroxyethyl-theophylline(etophylline), diphenhydramine and its hydrochloride, diltiazem and itshydrochlorid, and diphenylethyl(adenosine).

In a preferred embodiment, the dosage form according to the inventioncontains no substances which irritate the nasal passages and/or pharynx,i.e. substances which, when administered via the nasal passages and/orpharynx, bring about a physical reaction which is either so unpleasantfor the patient that he/she does not wish to or cannot continueadministration, for example burning, or physiologically counteractstaking of the corresponding active ingredient, for example due toincreased nasal secretion or sneezing. Further examples of substanceswhich irritate the nasal passages and/or pharynx are those which causeburning, itching, an urge to sneeze, increased formation of secretionsor a combination of at least two of these stimuli. Correspondingsubstances and the quantities thereof which are conventionally to beused are known to the person skilled in the art. Some of the substanceswhich irritate the nasal passages and/or pharynx are accordingly basedon one or more constituents or one or more plant parts of a hotsubstance drug. Corresponding hot substance drugs are known per se tothe person skilled in the art and are described, for example, in“Pharmazeutische Biologie—Drogen und ihre Inhaltsstoffe” by Prof. Dr.Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag,Stuttgart-New York, 1982, pages 82 et seq. The corresponding descriptionis hereby introduced as a reference and is deemed to be part of thedisclosure.

The dosage form according to the invention furthermore preferablycontains no antagonists for the physiologically active substance (A),preferably no antagonists against psychotropic substances, in particularno antagonists against opioids. Antagonists suitable for a givenphysiologically active substance (A) are known to the person skilled inthe art and may be present as such or in the form of correspondingderivatives, in particular esters or ethers, or in each case in the formof corresponding physiologically acceptable compounds, in particular inthe form of the salts or solvates thereof. The dosage form according tothe invention preferably contains no antagonists selected from among thegroup comprising naloxone, naltrexone, nalmefene, nalide, nalmexone,nalorphine or naluphine, in each case optionally in the form of acorresponding physiologically acceptable compound, in particular in theform of a base, a salt or solvate; and no neuroleptics, for example acompound selected from among the group comprising haloperidol,promethacine, fluphenazine, perphenazine, levomepromazine, thioridazine,perazine, chlorpromazine, chlorprothixine, zuclopenthixol, flupentixol,prothipendyl, zotepine, benperidol, pipamperone, melperone andbromperidol.

The dosage form according to the invention furthermore preferablycontains no emetic. Emetics are known to the person skilled in the artand may be present as such or in the form of corresponding derivatives,in particular esters or ethers, or in each case in the form ofcorresponding physiologically acceptable compounds, in particular in theform of the salts or solvates thereof. The dosage form according to theinvention preferably contains no emetic based on one or moreconstituents of ipecacuanha (ipecac) root, for example based on theconstituent emetine, as are, for example, described in “PharmazeutischeBiologie—Drogen und ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner,2nd, revised edition, Gustav Fischer Verlag, Stuttgart, New York, 1982.The corresponding literature description is hereby introduced as areference and is deemed to be part of the disclosure. The dosage formaccording to the invention preferably also contains no apomorphine as anemetic.

Finally, the dosage form according to the invention preferably alsocontains no bitter substance. Bitter substances and the quantitieseffective for use may be found in US-2003/0064099 A1, the correspondingdisclosure of which is incorporated herein and mare a part hereof.Examples of bitter substances are aromatic oils, such as peppermint oil,eucalyptus oil, bitter almond oil, menthol, fruit aroma substances,aroma substances from lemons, oranges, limes, grapefruit or mixturesthereof, and/or denatonium benzoate.

The dosage form according to the invention accordingly preferablycontains neither substances with a psychotropic action, nor substanceswhich irritate the nasal passages and/or pharynx, nor antagonists forthe physiologically active substance (A), nor emetics, nor bittersubstances.

In a preferred embodiment, the dosage form according to the inventioncontains a nutritional supplement as the physiologically activesubstance (A). Nutritional supplements preferably contain one or morenutrients in a concentrated, measured dose form which is atypical offoodstuffs. They are intended to supplement daily food intake in thosecases in which intake with the food is inadequate or supplementation isdesired. The nutritional supplement is preferably selected from thegroup consisting of vitamins, minerals, trace elements, enzymes, fattyacids, amino acids and antioxidants. Particularly preferred nutritionalsupplements are vitamins, provitamins and the derivatives thereof, inparticular retinol, calcitriol, tocopherol, phylloquinone, thiamine,riboflavine, folic acid, niacin (in particular nicotinamide),pantothenic acid, pyridoxal, cobalamin, L-ascorbic acid, biocytin,biotin and carotenoids.

Active Substance (A)

In a preferred embodiment, the dosage form according to the inventioncontains as the physiologically active substance (A) a pharmaceuticallyeffective amount of a pharmaceutical substance (=pharmaceutical activeingredient), which justifies use of the dosage form as a pharmaceuticalpreparation and is the cause of the activity thereof. Pharmaceuticalsubstances which may in principle be considered in the dosage formaccording to the invention are any known pharmaceutical substances,wherein the pharmaceutical substances may be present in the dosage formaccording to the invention as such, in the form the derivatives thereof,in particular esters or ethers, or in each case in the form ofcorresponding physiologically acceptable compounds, in particular in theform of the corresponding salts or solvates thereof, as racemates or ina form enriched in one or more stereoisomers (enantiomers ordiastereomers).

Particularly preferably the dosage form according to the inventioncontains a substance (A) or two or more substances (A) selected from thegroup consisting of

agents for the treatment and prevention of diseases of the alimentarysystem and metabolism [A]; in particular stomatological preparations[A01], agents for the treatment and prevention of acid-related disorders[A02], agents for the treatment and prevention of functionalgastrointestinal tract disorders [A03], serotonin 5HT₃ antagonists[A04AA], antihistamine preparations [A04AB], agents for bile and livertherapy [A05], laxatives [A06], intestinal antiinfectives [A07A],intestinal adsorbents [A07B], electrolytes with carbohydrates [A07C],intestinal antiinflammatory agents [A07E], microbial antidiarrhoeals[A07F], digestives including enzymes [A09], drugs used in diabetes[A10], vitamins [A11], minerals [A12], anabolic agents for systemicapplications [A14] and appetite stimulants [A15];

agents for the treatment and prevention of diseases of the blood and theblood forming organs [B]; in particular antithrombotic agents [B01],antihaemorrhagics [B02], antianaemic preparations [B03] and otherhaematological agents [B06];

agents for the treatment and prevention of diseases of thecardiovascular system [C]; in particular agents for cardiac therapy[C01], antihypertensives [C02], diuretics [C03], peripheralvasodilatators [C04], vasoprotectives [C05], antihypotensives [C06A],□-adrenoceptor antagonists [C07], calcium channel blockers [C08], agentsacting on the renin-angiotensin system [C09] and lipid reducing agents[C10];

dermatologicals [D]; in particular antifungals for systemic use [D01B],antipsoriatics for systemic use [D05B], antiacne preparations forsystemic use [D10B];

agents for the treatment and prevention of diseases of the genitourinarysystem and sex hormones [G]; in particular gynaecological antiinfectivesand antiseptics [G01], oxytocics [G02A], sympathomimetic labourrepressants [G02CA], prolactin inhibitors [G02CB], hormonalcontraceptives for systemic use [G03] and urologicals [G04];

systemic hormone preparations excluding sex hormones and insulins [H];in particular pituitary and hypothalamic hormones and analogue [H01],corticosteroids for systemic use [H02], thyroid preparations [H03],pancreatic hormones [H04], and agents for regulating calcium homeostatis[H05];

antiinfectives for systemic use [J]; in particular antibiotics forsystemic use [J01], antimycotics for systemic use [J02],antimycobacterials [J04], antivirals for systemic use [J05], immune seraand immunoglobulins [J06], and vaccines [J07]);

antineoplastic and immunomodulating agents [L] (in particularantineoplastistic agents [L01], agents for endocrine therapy [L02],immunostimulants [L03] and immunosuppressive agents [L04];

agents for the treatment and prevention of diseases of themusculo-skeletal system [M]; in particular antiinflammatory andantirheumatic agents [M01], peripherally acting muscle relaxants [M03A],directly acting muscle relaxants [M03C], antigout preparations [M04] andagents for the treatment of bone diseases [M05];

agents for the treatment and prevention of diseases of the nervoussystem [N]; in particular salicylic acid the derivatives thereof[N02BA], pyrazolones [N02BB], anilides [N02BE], ergot alkaloids [N02CA],corticosteroid derivatives [N02CB], selective serotonin-5HT₁ agonists[N02CC], hydantoin derivatives [N03AB], oxazolidine derivatives [N03AC],succinimide derivatives [N03AD], carboxamide derivatives [N03AF], fattyacid derivatives [N03AG], antiparkinson drugs [N04]), antipsychotics[N05A], antidepressants [N06A], antidementia drugs [N06D],parasympathomimetics [N07A] and antivertigo preparations [N07C];

antiparasitic products, insecticides and repellents [P]; in particularantiprotozoals [P01], anthelmintics [P02] and ectoparasiticides,including scabicides, insecticides and repellents [P03];

agents for the treatment and prevention of diseases of the respiratorysystem [R]; in particular nasal preparations [R01], throat preparations[R02], drugs for obstructive airways diseases [R03], expectorants,excluding combinations with cough suppressants [R05C] and antihistaminesfor systemic use [R06];

agents for the treatment and prevention of diseases of the sensoryorgans [S]; in particular otologicals [S02]; and

general diet products [V06] and therapeutic radiopharmaceuticals [V10],

wherein the abbreviations stated in square brackets here correspond tothe ATC Index, as used by the WHO for classifying pharmaceuticalsubstances (preferred version: January 2005 or 2006).

The dosage form according to the invention preferably contains asubstance (A) or two or more substances (A) selected from the groupconsisting of 4-aminomethylbenzoic acid, abacavir, abamectin, abciximab,abibendan, abrin, acamprosat, acarbose, acebutolol, aceclidine,aceclofenac, acediasulfone, acemetacin, acenocoumarol, acetazolamide,acetoacetic acid, acetyldigoxin, acetylandromedol, acetylcysteine,□-acetyldigoxin, acetylhistamine, acetylsalicylic acid,acetylthiocholine, aciclovir, acipimox, acitretin, aclarubicin,aconitine, acriflavinium chloride, acrivastine, actinoquinol,acylaminopenicillin, adalimumab, adapalene, adefovir, adefovirdipivoxil, adenosine, adenosine phosphate, adenosine triphosphate,adipiodone, adrenalin, aescin, agalsidase alfa, agalsidase beta,agaricic acid, ajmaline, alanine, albendazole, alcuronium, aldesleukin,aldosterone, alemtuzumab, alendronic acid, alfacalcidol, alfuzosin,algeldrate F, alitretinoin, alizapride, allantoin F, allopurinol, allylisorhodanate, almasilate F, almotriptan, □-acetyldigoxin, alprenolol,alprostadil, alteplase, aluminium glycinate F, aluminium hydroxide F,aluminium phosphate F, aluminium triformate, amantadine, ambazone,ambroxol, ambutonium bromide, formic acid, amicacin, amidephrine,amidotrizoic acid, amifostine, amikacin, amiloride, aminoacetic acid,aminoglutethimide, aminophylline, aminoquinuride, amiodarone,amisulpride, amitriptyline, amitryptiline, amlodipine, amorolfine,amoxicillin, amphotericin B, ampicillin, amprenavir, amylmetacresol,amyl nitrite, anagrelide, anakinra, anastrozole, ancrod, anistreplase,antazoline, antithrombin III, apomorphine, apraclonidine, aprepitant,aprindine, aprotinin, arcitumomab, arginine, aripiprazole, arsenictrioxide, artemether, articaine, ascorbic acid, asparagine,L-asparaginase, aspartic acid, atazanavir, atenolol, atomoxetine,atorvastatin, atosiban, atovaquone, atracurium, atracurium besylate,atropine, auranofin, azapropazone, azathioprine, azelaic acid,azelastine, azidothymidine, azithromycin, azlocillin, aztreonam, N2alanyl levoglutamide, p-aminosalicylic acid,

bacampicillin, bacitracin, baclofen, balsalazide, bambuterol, bamethan,bamipine, barbexaclone, barium sulfate F, barnidipine, basiliximab,batroxobin, becaplermin, beclomethasone, bendamustine, befunolol,bemiparin, benactyzine, benazepril, bencyclane, bendazac,bendroflumethiazide, benproperine, benserazide, benzaseride, benzathine,benzatropine, benzbromarone, benzocaine, benzoyl peroxide, benzyclane,benzydamine, benzylpenicillin, benzylphenyl glycolate, betacarotene,betahistidine, betahistine, betamethasone, bethanechol, betaxolol,bethanechol chloride, betiatide, bevacizumab, bexarotene, bezafibrate,bibenzonium bromide, bicalutamide, bicisate, bifonazole, bimatoprost,biperiden, bisoprolol, bivalirudin, bleomycin, blood clotting factorVII, VIII, IX, X, XIII, bornapine, bornaprine, bortezomib, bosentan,botulinum toxin type B, brimonidine, brinzolamide, brivudin, bromhexine,bromocriptine, bromperidol, brompheniramine, brotizolam, budesonide,budipine, bufexamac, buflomedil, bumetanide, bunazosin, buphenine,bupivacaine, bupranolol, bupropion, buserelin, buspirone, busulfan,butalamine, butanilicaine, butenafine, butethamate, butinoline,butizide, butylscopolaminium,

5-chlorcarvacrol, C1 esterase inhibitor, cabergoline, cadexomer iodine,cafedrine, calcipotriol, calcitonin, calcitriol, camylofine, candesartancilexetil, canrenoic acid, capecitabine, capreomycin, capsaicin,captopril, carazolol, carbaldrate F, carbamazepine, carbasalate calcium,carbenoxolone, carbidopa, carbimazole, carbinoxamine, carboplatin,carglumic acid, carmustine, caroverine, carteolol, carvedilol,caspofungin, cefaclor, cefadroxil, cefalexin, cefaloridine, cefamandole,cefazolin, cefdinir, cefepime, cefetamet-pivotil, cefixime, cefodizime,cefoperazone, cefotaxime, cefotiam, cefoxitin, cefpirome, cefpodoxime,cefpodoxime-proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefuroxime, celecoxib, celiprolol, certoparin, cetirizine,cetrimide, cetrimonium bromide, cetrorelix, cetuximab, cetylpyridinium,chenodeoxycholic acid, quinidine, quinine, quinine iron citrate F,quinine tannate F, chlorambucil, chloramphenicol, chlorobutynol,chlorhexidine, chlormidazole, chlorobutanol, chloroquine, chloroxylenol,chlorphenamine, chlorphenesin, chlorphenoxamine, chlorpromazine,chlorprotheaxine, chlorprothixine, chlortalidone, chlortetracycline,chlorzoxazone, choline, chondroitin sulfate, choriogonadotropin alfa,chorionic gonadotropin, chrysarobin, chymotrypsin, ciclesonide,cicletanine, ciclopirox, ciclosporin, cidofovir, cilastatin, cilazapril,cimetidine, cinacalcet, cinchocaine, cinnarizine, cinolazepam,ciprofloxacin, cisapride, cisatracurium besylate, cisplatin, citalopram,citicoline, cladribine, clarithromycin, clavulanic acid, clemastine,clenbuterol, clindamycin, clioquinol, clobetasol, clobetasone,clobutinol, clocortolone, clodronic acid, Clofibrate, clomifene,clomipramine, clonazepam, clonidine, clopamide, clopidogrel, clostebolacetate, clostridium botulinum, clotrimazole, cloxiquine, clozapine,cocarboxylase, colchicine, colecalciferol, colesevelam, colestipol,colestyramine, colfosceril palmitate, colistin, zinc eyewash F,corticorelin, corticotrophin, cortisone, cresol, croconazole,cromoglicic acid, crotamiton, cryofluorane, coumarin, cyanamide,cyanocobalamin, cyclizine, cyclobutyrol, cyclopentolate,cyclophosphamide, cycloserine, cyproheptadine, cyproterone, cysteine,cytarabine, cytarabine,

2,4-dichlorobenzyl alcohol, 2-diethylaminoethanol, dacarbazine,daclizumab, dactinomycin, dalfopristin, dalteparin, danaparoid, danazol,dantrolene, dapiprazole, dapsone, darbepoetin alfa, darifenacin,Daunorubicin, deanol, deanolace, decarbazine, dectaflur F, deferiprone,deferoxamine, delapril, demeclocycline, denaverine, depreotide,dequalinium, desflurane, desipramine, desirudin, deslanoside,desloratadine, desmeninol, desmopressin, desogestrel, desoximetasone,deoxyribonuclease, detajmium, dexamethasone, dexchlorpheniramine,dexibuprofen, dexketoprofen, dexrazoxane, dextran, dextromethorphan,diacerein, diacetyl morphine, dibenzepin, dibotermin alfa, diclofenac,diclofenamide, didanosine, dienestrol, dienogest, diethylstilbestrol,difloxacin, diflucortolone, diflunisal, digitoxin, digoxin,dihydralazine, dihydroergocornine, dihydroergocristine,dihydroergocryptine, dihydroergotamine, dihydroergotoxine,dihydrotachysterol, diisopropylamine, dipotassium clorazepate,diltiazem, dimenhydrinate, dimepranol, dimercaprol, dimethyl sulfoxide,dimethindene, disodium selenite, dinoprost, dinoprostone, diosmin,diphenhydramine, diphenoxylate, diphenylpyraline, dipivefrine,diprophylline, dipyridamole, disopyramide, dinitrogen monoxide,distigmine, disulfiram, dithranol, dixyrazine, D-norpseudoephedrine,dobesilate calcium, dobutamine, docetaxel, dofetilide, dolasetron,domperidone, donepezil, dopamine, dopexamine, dornase alfa, dorzolamide,dosulepin, doxapram, doxazosin, doxepin, doxorubicin, doxycycline,doxylamine, drofenine, droperidol, drospirenone, drotrecogin alfa,duloxetine, dutasteride, dydrogesterone, N,N′-dihydroxymethyl urea,

ebastine, econazole, ecothiopate iodide, efalizumab, efavirenz,eflornithine, iron(III) ammonium citrate F, superparamagnetic ironoxide, elcatonin, eletriptan, emedastine, emepronium, emeproniumcarrageenate, emetine, emtricitabine, enalapril, enalaprilat, enflurane,enfuvirtide, enoxacin, enoxaparin, entacapone, ephedrine, ephedrineracephedrine, epinastine, epinephrine, epirubicin, eplerenone, epoetinalfa, epoetin beta, epoetin delta, epoprostenol, eprazinone, eprosartan,eptacog alfa, eptifibatide, eptotermin alfa, erdosteine, ergocalciferol,ergometrine, ergotamide, ertapenem, erythromycin, escitalopram, esmolol,esomeprazole, estradiol, estramustine, estriol, estrone, etacrynic acid,etamivan, etanercept, ethacridine, ethambutol, ethaverine,ethinylestradiol, ethisterone, ethosuximide, etidronic acid, etilefrine,etodolac, etofenamate, etofibrate, etofylline, etomidate, etonogestrel,etoposide, etoricoxib, everolimus, exametazime, exemestane, ezetimibe,

3-fluorotyrosine, famciclovir, famotidine, felbamate, felbinac,felodipine, fenbufene, fendiline, fenofibrate, fenoterol, fenticonazole,fexofenadine, fibrinogen, fibrinolysin, filgrastim, finasteride,flavoxate, flecainide, flucloxacillin, fluconazole, fludarabine,fludeoxyglucose [¹⁸F], fludrocortisone, flufenamic acid, flumazenil,flumetasone, flunarizine, flunisolide, fluocinolone acetonide,fluocinonide, fluocortolone, fluophenozine, fluorescein dilaurate,fluorescein sodium, fluorometholone, fluorouracil, fluorophosphoricacid, fluorosilane, fluoxetil, fluoxetine, flupentixol, fluphenazine,flupirtine, fluprednidene, flurbiprofen, flutamide, fluticasone,flutrimazole, fluvastatin, fluvoxamine, folic acid, follitropin alfa,follitropin beta, folic acid, fomepizole, fomivirsen, fondaparinux,formestane, formoterol, fosamprenavir, foscarnet, fosfestrol,fosfomycin, fosinopril, fosphenyloin, fotemustine, framycetin,framycetin, frovatriptan, fulvestrant, furosemide, fusafungine, fusidicacid, fytic acid,

gabapentin, gadobenic acid, gadobutrol, gadodiamide, gadopentetic acid,gadoteridol, gadoteric acid, gadoteric acid-meglumine, gadoxetic acid,galantamine, gallopamil, ganciclovir, ganirelix, gatifloxacin,gemcitabine, gemfibrozil, gentamicin, gepefrine, gestodene, glatiramer,glibenclamide, glibornuride, gliclazide, glimepiride, glipizide,gliquidone, glisoxepide, glucagon, glutamine, glutamic acid,glycopyrronium, glycopyrronium bromide, glycyrrhetinic acid,gonadorelin, goserelin, gramicidin, granisetron, grepafloxacin,griseofulvin, g-strophanthin, guajacol, guanethidine, guanfacine,

¹³C urea, 4-hydroxybutyric acid, halcinonide, halofantrine,halometasone, haloperidol, halothane, haem, haematoporphyrin, heparin,hepatitis B vaccine, heptaminol, hexobarbital, hexobendine,hexoprenaline, histamine, histidine, homatropine, homofenazine, humanalbumin, hyaluronidase, hydralazine, hydrastinine, hydroquinone,hydrochlorothiazide, hydrocortisone, hydrotalcite F, hydroxocobalamin,hydroxycarbamide, hydroxychloroquine, hydroxycine, hydroxylamine,hydroxyprogesterone, hydroxyzine, hymecromone,

ibandronic acid, ibopamine, ibritumomab tiuxetan, ibuprofen, ibutilide,idarubicin, ifosfamide, iloprost, imatinib, imatinib mesylate,imidapril, imiglucerase, imipenem, imipramine, imiquimod, immunocyanin,indanazoline, indapamide, indinavir, indium chloride [¹¹¹In], indobufen,indometacin, indoramin, infliximab, inosine, insulin, insulin aspart,insulin detemir, insulin glargine, insulin glulisine, insulin lispro,interferon alfa, interferon alfa-2b, interferon alfacon-1, interferonbeta, interferon beta-1a, interferon beta-1b, interferon gamma,iobitridol, iodine, iodamide, iodixanol, ioflupane [¹²³I], iohexol,iomeprol, iopamidol, iopentol, iopromide, iosarcol, iotrolan, iotroxicacid, ioversol, ioxaglic acid, ioxitalamic acid, ipatropium, irbesartan,irinotecan, irinotecan, isepamicin, isoaminile, isoconazole, isoflurane,isoleucine, isoniazid, isonicotinic acid, isoprenaline, isosorbide,isospaglumic acid, isotretinoin, isoxsuprine, isradipine, itraconazole,

josamycin,

potassium permanganate, kallidinogenase, kanamycin, kawain, kebuzone,ketamine, ketoconazole, ketoprofen, ketorolac, ketotifen, collagenase,creosote,

labetalol, lacidipine, lactitol, lamivudine, lamotrigine, lanreotide,lansoprazole, laronidase, latanoprost, leflunomide, lenograstim,lepirudin, lercanidipine, letrozole, leucine, leuprorelin, levallorphan,levamisole, levetiracetam, levobunolol, levobupivacaine, levocabastine,levocetirizine, levodopa, levofloxacin, levofolinate calcium,levomepromazine, levomethadyl, levonorgestrel, levopropylhexedrine,levosimendan, levothyroxine, lidocaine, lincomycin, lindane, linezolid,liothyronine, lisinopril, lisuride, lobeline, Iodoxamide, lofepramine,lomefloxacin, lomustine, lonazolac, loperamide, lopinavir, loratadine,lorazepam oxide, lornoxicam, losartan, loteprednole, lovastatin,lumefantrine, lutropin alfa, lymecycline, lynestrenol, lypressin,lysine,

magaldrate F, magnesium pidolate, magnesium L-aspartate, mangafodipir,manidipine, maprotiline, mebendazole, mebeverine, meclofenoxate,mecloxamine, meclozine, medrogestone, medroxyprogesterone, mefenamicacid, mefloquine, megestrol, melagatrane, melitracen, melperol,melperone, melphalan, memantine, menadione, mepacrine, mepartricin,mephenyloin, mepindolol, mepivacaine, mepyramine, mequinol,mercaptamine, mercaptopurine, meropenem, mesalazine, mesna, mesterolone,mesuximide, metaclazepam, metamizole, metamphetamine, metenolone,metenolone acetate, metformin, methanthelinium, methazolamide,methenamine, methionine, methohexital, methotrexate, 5-methoxypsoralen,8-methoxypsoralen, methyl 5-aminolevulinate, methylbenactyzium bromide,methyldopa, methylergometrine, methylprednisolone, methylrosanilinium,methyltestosterone, methylthionium chloride, methysergide, metildigoxin,metipranolol, metoclopramide, metoprolol, methixene, metronidazole,mexiletine, mezlocillin, mianserine, miconazole, midodrine,mifepristone, miglitol, miglustat, milnacipran, milrinone, miltefosine,minocycline, minoxidil, mirtazapine, misoprostol, mitobronitol,mitomycin, mitotane, mitoxantrone, mivacurium chloride, mivacuronium,mizolastine, moclobemide, moexipril, molgramostim, molsidomine,mometasone, monochloroacetic acid, montelukast, moroctocog alfa,moxaverine, moxifloxacin, moxonidine, mupirocin, mycophenolate mofetil,

nadifloxacin, nadrolon decanonate, nadroparin calcium, naftidrofuryl,naftifine, nalbuphine, nalide, nalmefene, nalmexone, naloxone,naltrexone, naluphine, naphazoline, 2naphthol, naproxen, naratriptan,naratriptan, nateglinide, sodium aurothiomalate, sodium phenylbutyrate,sodium fluoride, sodium hyaluronate, sodium iodide [¹³¹I], sodiummolybdate [⁹⁹Mo], sodium phenylbutyrate, n-butyl-p-aminobenzoate,N-butylscopolaminium bromide, nebivolol, nedocromil, nefazodone,nefopam, nelfinavir, neomycin, neostigmine, neostigmine methylsulfate,netilmicin, nevirapine, n-heptyl-2-phenyl glycinate, nicardipine,nicergoline, nicethamide, niclosamine, nicoboxil, nicorandil, nicotine,nicotine aldehyde, nicotinamide, nicotine resinate, nicotinic acid,nicotinic acid ester, nicotinyl alcohol, nifedipine, niflumic acid,nifuratel, nilvadipine, nimesulide, nimodipine, nimorazole, nimustine,nisoldipine, nitisinone, nitrendipine, nitric oxide, nitrofurantoin,nitroglycerine, nizatidine, N-methylephedrine, nonacog alfa, nonivamide,noradrenalin, norelgestromin, norepinephrine, norethisterone,norfenefrine, norfloxacin, norgestimate, norgestrel, nortriptyline,noscapine, nystatin,

obidoxime chloride, octafluoropropane, octocog alfa, octodrine,octreotide, odansetron, ofloxacin, olaflur F, olanzapine, olmesartanmedoxomil, olopatadine, olsalazine, omeprazole, omoconazole,ondansetron, opipramol, oral cholera vaccine, orciprenaline, orlistat,ornipressin, orphenadrine, oseltamivir, osteogenic protein-1: BMP-7,oxaprozin, oxatomide, oxcarbazepine, oxedrine tartrate, oxetacaine,oxiconazole, oxilofrine, oxitropium, 2-oxo-3-methylbutyric acid,2-oxo-3-methylvaleric acid, 2-oxo-3-phenylpropionic acid,2-oxo-4-methylvaleric acid, oxprenolol, oxybuprocaine, oxybuprocaine,oxybutynin, oxybutynin, oxyfedrine, oxymetazoline, oxytetracycline,oxytocin,

paclitaxel, palinavir, palivizumab, palonosetrone, pamidronic acid,pancuronium, pantoprazole, papaverine, paracetamol, paraldehyde,parecoxib, paricalcitol, parnaparin, paromomycin, paroxetine,pefloxacin, pegfilgrastim, peginterferon alfa, pegvisomant, pemetrexed,penbutolol, penciclovir, penfluridol, penicillamine, benperidol,pentaerithrityl tetranitrate, pentamidine, pentetrazol, pentetreotide,pentosan polysulfate sodium, pentoxifylline, pentoxyverine, perazine,perchloric acid, perflenapent, perflisopent, perflutren, pergolide,perindopril, perphenazine, phenacetin, phenamazid, phenazone,phenazopyridine, pheniramine, phenol, phenolphthalein, phenoxybenzamine,phenoxymethylpenicillin, phenprocoumon, phentolamine, phenylalanine,phenylbutazone, phenylephrine, phenylpropanolamine, phenyltoloxamine,phenyloin, phloroglucinol, pholedrine, phthalylsulfathiazole,physostigmine, phytomenadione, phytosterol, picric acid, pilocarpine,pimecrolimus, pimozide, pinaverium bromide, pindolol, pioglitazone,pipamperone, pipazetate, pipecuronium bromide, pipemidic acid,pipenzolate, piperacillin, piprinhydrinate, piracetam, pirarubicin,pirbuterol, pirenzepine, piritramide, piroxicam, pivmecillinam,pizotifen, podophyllotoxin, polidocanol, polycarbophil, polyestradiolphosphate, polymyxin B, polymyxin-B, polystyrenesulfonic acid, porfimer,prajmaline, prajmalium bitartrate, pramipexole, pranoprofen, prasterone,pravastatin, prazepam, prazosin, prednicarbate, prednisolone,prednisone, pregabalin, proglumetacin, pridinol, prilocalne, primaquine,primidone, prithipendyl, procaine, procainamide, procarbazil,procarbazine, procyclidin, progesterone, proglumetacin, proglumide,proguanil, proline, promethazine, propacetamol, propafenon, propanolol,propicillin, propiverine, propofol, propranolol, propylthiouracil,propyphenazone, protamine, protamine sulfate, protein C, prothipendyl,prothrombin, protionamide, protirelin, proxymetacaine, proxyphylline,pseudoephedrine, Pulmonal, pyrantel, pyrazinamide, pyridostigmine,pyridostigmine bromide, pyridoxine, 3-pyridylmethanol, pyrimethamine,pyrithione zinc, pyritinol, pyrogallol, pyrvinium, pyrvinium embonate,

mercury amide chloride, quetiapine, quinagolide, quinapril,quinupristin,

rabeprazole, racephedrine, racecadotrile, raloxifene, raltitrexed,ramipril, ranitidine, rasagiline, rasburicase, raubasine, reboxetine,repaglinide, reproterol, reserpine, resorcinol, reteplase, retinol,reviparin, ribavirin, riboflavin, rifabutin, rifampicin, rifamycin,rifaximin, rilmenidine, riluzole, rimexolone, risedronic acid,risperidone, ritonavir, rituximab, rivastigmine, rizatriptan, rocuroniumbromide, rofecoxib, ropinirole, ropivacaine, ropivacaine, rosiglitazone,red mercuric sulfide F, roxatidine, roxithromycin,

salbutamol, salicylic acid, salmeterol, nitric acid, nitrous acid,salverine, samarium [¹⁵³Sm] lexidronam, saquinavir, sulfur hexafluoride,scopolamine, selegiline, selenium sulfide, serine, sermorelin,sertaconazole, sertindole, sertraline, sevelamer, sevoflurane,sibutramine, silver chloride F, sildenafil, silibinin, simvastatin,sirolimus, formaldehyde solution, solifenacine, somatostatin,somatropin, sotalol, spaglumic acid, sparteine, spectinomycin,spiramycin, spirapril, spironolactone, stavudine, streptodornase,streptokinase, streptomycin, strontium ranelate, strontium chloride,strychnine, sucralfate F, sulbactam, sulesomab, sulfacetamide,sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfamerazine,sulfamethoxazole, sulfamethoxydiazine, sulfametrole, sulfanilamide,sulfasalazine, sulfathiazole, sulfisomidine, sulindac, sulodexide,sulfur hexafluoride, sulpiride, sulprostone, sultamicillin, sultiame,sumatriptan, suxamethonium,

tacalcitol, tacrolimus, tadalafil, tamoxifen, tamsulosin, tasonermin,taurolidine, tazarotene, tazobactam, tegafur, teicoplanin,telithromycin, telmisartan, temoporfin, temozolomide, tenecteplase,teniposide, tenofovir, tenofovir disoproxil, tenoxicam, terazosin,terbinafine, terbutaline, terfenadine, teriparatide, terizidone,terlipressin, testosterone, testosterone propionate, testosteroneundecanoate, tetracaine, tetracosactide, tetracycline,tetrafluoroborate-1+, tetrofosmin, tetryzoline, thallium chloride[²⁰¹Tl], theobromine, theodrenaline, theodrenaline, theophylline,thiamazole, thiamine, thiethylperazine, thiocolchicoside, thiopental,thioridazine, thiotepa, threonine, thrombin, thrombokinase, thymol,thyrotropin alfa, tiagabine, tianeptine, tiapride, tibolone,ticlopidine, tiludronic acid, timolol, tinzaparin, tioconazole,tioguanine, tiotropium bromide, tirilazad, tirofiban, tisopurine,tizamidine, tizanidine, tobramycin, tocainide, tolazoline, tolbutamide,tolcapone, tolfenamic acid, tolmetin, tolperisone, tolterodine,topiramate, topotecan, torasemide, toremifene, tramazoline,trandolapril, tranexamic acid, tranylcypromine, trapidil, trastuzumab,travoprost, trazodone, tretinoin, triamcinolone, triamcinoloneacetonide, triamterene, trichloroacetic acid, triethylperazine,trifluoperazine, triflupromazine, trihexyphenidyl, trimebutine,trimecaine, trimegestone, trimetazidine, trimethoprim, trimipramine,tripelennamine, triprolidine, triptorelin, tritoqualine, trofosfamide,tromantadine, trometamol, tropicamide, tropisetron, trospium,tryptophan, tubocurarine chloride, tulobuterol, tyloxapol, tyrosine,tyrothricin,

unoprostone, urapid, urapidil, urokinase, ursodeoxycholic acid,

valaciclovir, valdecoxib, valganciclovir, valine, valproic acid,valsartan, vancomycin, vardenafil, vecuronium, vecuronium bromide,venlafaxine, verapamil, verteporfin, vigabatrin, viloxazine,vinblastine, vincamine, vincristine, vindesine, vinorelbine,vinpocetine, viquidil, voriconazole, votumumab,

hydrogen peroxide,

xantinol nicotinate, ximelagatrane, xipamide, xylometazoline,

yohimbine, yttrium ⁹⁰Y chloride,

zalcitabine, zaleplon, zanamivir, zidovudine, zinc acetate dihydrate,zinc chloride, zinc citrate, zinc sulfate, ziprasidone, zofenopril,zoledronic acid, zolmitriptan, zolpidem, zolpidem tartrate, zonisamide,zopiclone, zotepine, zucklopantexol, and zuclopenthixol.

The above-stated compounds are predominantly stated by theirinternational nonproprietary name (INN) and are known to the personskilled in the art. Further details may be found, for example, byreferring to International Nonproprietary Names (INN) for PharmaceuticalSubstances, World Health Organization (WHO).

In a preferred embodiment the dosage form according to the inventioncontains one physiologically active substance (A) or morephysiologically active substances (A) selected from the group consistingof1,1-(3-dimethylamino-3-phenylpentamethylen)-6-fluor-1,3,4,9-tetrahydropyrano[3,4-b]indole,in particular its hemicitrate;1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1,3,4,9-tetrahydropyrano[3,4-b]indole,in particular its citrate; and1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1,3,4,9-tetrahydropyrano[3,4-b]-6-fluoro-indole,in particular its hemicitrate. These compounds are known, for example,from WO 2004/043967 or WO 2005/066183. The corresponding descriptionsare hereby introduced as a reference and are deemed to be part of thedisclosure.

Wax

At least one natural, semi-synthetic or synthetic wax (D) (=component(D)) may be used in order to achieve the necessary breaking strength ofthe dosage form according to the invention. Preferred waxes are thosewith a softening point of at least 50° C., or of at least 55° C., or ofat least 60° C., or of at least 65° C. or of at least 70° C. Carnaubawax and beeswax are particularly preferred. Carnauba wax is veryparticularly preferred. Carnauba wax is a natural wax which is obtainedfrom the leaves of the carnauba palm and has a softening point of atleast 80° C. When the wax component is additionally used, it is usedtogether with at least one polymer (C) in quantities such that thedosage form has a breaking strength of at least 400 N, preferably of atleast 500 N.

Auxiliary Substances (B)

Auxiliary substances (B) which may be used are those known auxiliarysubstances which are conventional for the formulation of solid dosageforms. These are preferably plasticisers, such as triacetin andpolyethylene glycol, preferably a low molecular weight polyethyleneglycol, auxiliary substances which influence active ingredient release,preferably hydrophobic or hydrophilic, preferably hydrophilic polymers,very particularly preferably hydroxypropylmethylcellulose, and/orantioxidants. Polymers, particularly preferably cellulose ethers,cellulose esters and/or acrylic resins are preferably used ashydrophilic matrix materials. Ethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivativesthereof, such as the salts, amides or esters thereof are veryparticularly preferably used as matrix materials.

Suitable antioxidants are ascorbic acid, butylhydroxyanisole (BHA),butylhydroxytoluene (BHT), salts of ascorbic acid, monothioglycerol,phosphorous acid, vitamin C, vitamin E and the derivatives thereof,sodium bisulfite, particularly preferably butylhydroxytoluene orbutylhydroxyanisole and α-tocopherol.

The antioxidant is preferably used in quantities of 0.01 to 10 wt. %,preferably of 0.03 to 5 wt. %, relative to the total weight of thedosage form.

Dosage Forms

The dosage forms according to the invention are distinguished in that,by virtue of their resistance to crushing, they cannot be pulverisedwith the assistance of conventional comminution tools, such as a pestleand mortar. Overdosing is consequently virtually ruled out. However, inorder to increase the resistance to crushing of the dosage form stillfurther, the dosage forms according to the invention may contain furtherresistance-to-crushing-enhancing agents as auxiliary substances (B).

The dosage form according to the invention is preferably solid andsuitable for taking orally, vaginally or rectally, preferably orally.The dosage form is preferably not in film form. In a further preferredembodiment, the dosage form according to the invention assumes the formof a tablet, a capsule or the form of an oral osmotic therapeutic system(OROS).

In a preferred embodiment, the dosage form according to the inventionassumes the form of a tablet.

The dosage form according to the invention may assume multiparticulateform, preferably the form of microtablets, microcapsules, micropellets,granules, spheroids, beads or pellets, optionally packaged in capsulesor press-formed into tablets, preferably for oral administration. Theindividual particles themselves exhibit a resistance to crushing of atleast 400 N, optionally also a tablet obtained therefrom.

The multiparticulate forms preferably have a size or size distributionin the range from 0.1 to 3 mm, particularly preferably in the range from0.5 to 2 mm. Depending on the desired dosage form, conventionalauxiliary substances (B) are optionally also used for the formulation ofthe dosage form.

Process of Preparation

The dosage form according to the invention may be produced by differentprocesses, which are explained in greater detail below; the presentinvention also relates to dosage forms that are obtainable by any of theprocesses described here below:

In general, the process for the production of the dosage form accordingto the invention preferably comprises the following steps:

mixing of component (A), (C), optionally (B) and optionally (D);

optionally preforming the mixture obtained from step (a), preferably byapplying heat and/or force to the mixture obtained from step (a), thequantity of heat supplied preferably not being sufficient to heatcomponent (C) up to its softening point;

hardening the mixture by applying heat and force, it being possible tosupply the heat during and/or before the application of force and thequantity of heat supplied being sufficient to heat component (C) atleast up to its softening point;

(d) optionally singulating the hardened mixture;

(e) optionally shaping the dosage form; and

(f) optionally providing a film coating.

Heat may be supplied directly or with the assistance of ultrasound.Force may be applied and/or the dosage form may be shaped for example bydirect tabletting or with the assistance of a suitable extruder,particularly by means of a screw extruder equipped with two screws(twin-screw-extruder) or by means of a planetary gear extruder.

In general, when the dosage formed is prepared utilizing an extruder,the following parameters are critical in extrusion processes and havethe consequences described.

1. Throughput (kg Per Hour)

If the throughput is too low the extruder is not correctly filled andthe material is stressed thereby affecting the viscosity and the releaseprofile of the final product If the throughput is too high, the load ofthe extruder is higher than 100% and the extruder shuts downautomatically; and if the throughput is tolerable but close to the upperlimit significant expansion of the extruded strand occurs (also known as“die swelling”).

2. Screw Geometry

A minimum number of kneading elements is required in order to obtain ahomogeneous mixture; if the number is too high, the material is stressedthereby affecting the viscosity and the release profile of the finalproduct. The number and lead of the conveying elements influences thehomogeneity of the mixture and its residence time in the extruder andcontrols the increase of the pressure in front of the die. Mixingelements improve the homogeneity of the mixture; and eccentric screwheads allow for a continuous discharge of the extrudate without densityvariations.

3. Die and Merge Element Geometry

The geometry of the element which merges the extrusion strands in frontof the die, and geometry of the die itself, the residence time in saidelement, and the ratio length of the die to diameter of the dieinfluence the compression of the material thereby affecting the meltpressure. The die pressure depends on revolution, throughput and melttemperature and affects the viscosity and the release profile of thefinal product.

4. Temperature (Melt Zones)

The feeding cylinder should not be heated to prevent the startingmaterial from melting in the feeder and causing an accumulation. Thenumber of cylinders is variable, the longer the extruder the longer theresidence time. The temperature of the cylinders (except feedingcylinder) destroys the material if it is too high; if too low thematerial dos not sufficiently melt thereby resulting in an inhomogeneousmixture and degradation. If the die temperature, if separately set toolow, causes the “extrusion skin” to not properly form thereby makingfurther processing of the extrudate difficult.

5. Revolution of the Extruder

If the extruder revolution speed is too high the material is stressedthereby affecting the viscosity and the release profile of the finalproduct. If the extruder revolution speed is too low the load of theextruder is higher than 100% and the extruder shuts down automatically;and inter alia the residence time depends on the revolution.

6. Arrangement of Cylinders

The position of feeding cylinder, the length of extruder are important.The degassing should be located close to the feeder in order to avoidair pockets in the product; and if one of the components isthermo-labile it may be separately fed into one of the rear cylinders.

7. Temperature of Cooling Water

Cooling of the engine and control of the temperature of the extrusioncylinders are important parameters.

The following process variants are preferred embodiments of the varioustechniques which may be utilized to produce the dosage forms:

PROCESS EMBODIMENT 1

In this embodiment, the dosage form according to the invention ispreferably produced without using an extruder by preferably mixingcomponents (A), (C), optionally (B) and the optionally present component(D) and, optionally after granulation, shaping the resultant mixture byapplication of force to yield the dosage form with preceding and/orsimultaneous exposure to heat.

This heating and application of force for the production of the dosageform proceeds without using an extruder.

Components (A), (C), optionally (B) and optionally (D) are mixed in amixer known to the person skilled in the art. The mixer may, forexample, be a roll mixer, shaking mixer, shear mixer or compulsorymixer.

The resultant mixture is preferably directly shaped into the dosage formaccording to the invention by application of force with preceding and/orsimultaneous exposure to heat. The mixture may, for example, be formedinto tablets by direct tabletting. In direct tabletting with precedingexposure to heat, the material to be pressed is heated immediately priorto tabletting at least to the softening temperature of component (C) andthen pressed. In the case of direct tabletting with simultaneousapplication of heat, the mixture to be press-formed is heated at leastto the softening point of polymeric component (C) with the assistance ofthe tabletting tool, i.e. the bottom punch, top punch and the die, andis so press-formed.

By such process using a tabletting tool with bottom punch, top punch anddie for tablets having a diameter of 10 mm and a radius of curvature of8 mm, e.g. 300 mg of a powder mixture may be compressed at a temperatureof e.g. 80° C., the pressure caused by a force of e.g. 2 kN or 4 kNbeing maintained for e.g. 15 seconds.

The resultant mixture of components (A), (C), optionally (B) andoptionally component (D) may also first be granulated and then, withpreceding and/or simultaneous exposure to heat, be shaped into thedosage form according to the invention by application of force.

When force is applied, it is applied until the dosage form has achieveda resistance to crushing of at least 400 N, 420 N, 440 N, 460 N, 480 N,or preferably of at least 500 N.

Granulation may be performed in known granulators by wet granulation ormelt granulation.

Each of the above-mentioned process steps, in particular the heatingsteps and simultaneous or subsequent application of force for productionof the dosage form according to the invention proceeds without using anextruder.

PROCESS EMBODIMENT 2

In this process variant, the dosage form according to the invention isproduced by thermoforming with the assistance of an extruder, withoutthere being any observable consequent discoloration of the extrudate.

In order to investigate the extent of discoloration due to thisthermoforming, the color of the mixture of starting components of whichthe dosage form consists is first determined without addition of acolor-imparting component, such as for example a coloring pigment or anintrinsically coloured component (for example α-tocopherol). Thiscomposition is then thermoformed according to the invention, wherein allprocess steps, including cooling of the extrudate, are performed underan inert gas atmosphere. By way of comparison, the same composition isproduced by the same process, but without an inert gas atmosphere. Thecolor of the dosage form produced according to the invention from thestarting composition and of the dosage form produced by way ofcomparison is determined. The determination is performed with theassistance of “Munsell Book of Color” from Munsell Color CompanyBaltimore, Md., USA, 1966 edition. If the colour of the dosage formthermoformed according to the invention has a color with identificationno. N 9.5, but at most a color with the identification no. 5Y 9/1,thermoforming is classed as being “without discoloration”. If the dosageform has a color with the identification no. 5Y 9/2 or greater, asdetermined according to the Munsell Book of Color, the thermoforming isclassed as being “with discoloration”.

Surprisingly, the dosage forms according to the invention exhibit nodiscoloration classed in accordance with the above classification, ifthe entire production process is performed under an inert gasatmosphere, preferably under a nitrogen atmosphere with the assistanceof an extruder for thermoforming.

This variant according to the invention for the production of dosageforms according to the invention is characterised in that

z) components (A), (C), optionally (B) and the optionally presentcomponent (D) are mixed,

y) the resultant mixture is heated in the extruder at least up to thesoftening point of component (C) and extruded through the outlet orificeof the extruder by application of force,

x) the still plastic extrudate is singulated and formed into the dosageform or

w) the cooled and optionally reheated singulated extrudate is formedinto the dosage form,

wherein process steps y) and x) and optionally process steps z) and w)are performed under an inert gas atmosphere, preferably a nitrogenatmosphere.

Mixing of the components according to process step z) may also proceedin the extruder.

Components (A), (C), optionally (B) and optionally (D) may also be mixedin a mixer known to the person skilled in the art. The mixer may, forexample, be a roll mixer, shaking mixer, shear mixer or compulsorymixer.

Before blending with the remaining components, component (C) and theoptionally present component (D) is preferably provided according to theinvention with an antioxidant. This may proceed by mixing the twocomponents, (C) and the antioxidant, preferably by dissolving orsuspending the antioxidant in a highly volatile solvent andhomogeneously mixing this solution or suspension with component (C) andthe optionally present component (D) and removing the solvent by drying,preferably under an inert gas atmosphere.

The, preferably molten, mixture which has been heated in the extruder atleast up to the softening point of component (C) is extruded from theextruder through a die with at least one bore.

The process according to the invention requires the use of suitableextruders, preferably screw extruders. Screw extruders which areequipped with two screws (twin-screw-extruders) are particularlypreferred.

The extrusion is preferably performed so that the expansion of thestrand due to extrusion is not more than 50%, i.e. that when using a diewith a bore having a diameter of e.g. 6 mm, the extruded strand shouldhave a diameter of not more than 9 mm. More preferably, the expansion ofthe strand is not more than 40%, still more preferably not more than35%, most preferably not more than 30% and in particular not more than25%. It has been surprisingly found that if the extruded material in theextruder is exposed to a mechanical stress exceeding a certain limit, asignificant expansion of the strand occurs thereby resulting inundesirable irregularities of the properties of the extruded strand,particularly its mechanical properties.

The extruder preferably comprises at least two temperature zones, withheating of the mixture at least up to the softening point of component(C) proceeding in the first zone, which is downstream from a feed zoneand optionally mixing zone. The throughput of the mixture is preferablyfrom 2.0 kg to 8.0 kg/hour.

After heating at least up to the softening point of component (C), themolten mixture is conveyed with the assistance of the screws, furtherhomogenised, compressed or compacted such that, immediately beforeemerging from the extruder die, it exhibits a minimum pressure of 5 bar,preferably of at least 10 bar, and is extruded through the die as anextruded strand or strands, depending on the number of bores which thedie comprises. The die geometry or the geometry of the bores is freelyselectable. The die or the bores may accordingly exhibit a round, oblongor oval cross-section, wherein the round cross-section preferably has adiameter of 0.1 mm to 15 mm and the oblong cross-section preferably hasa maximum lengthwise extension of 21 mm and a crosswise extension of 10mm. Preferably, the die or the bores have a round cross-section. Thecasing of the extruder used according to the invention may be heated orcooled. The corresponding temperature control, i.e. heating or cooling,is so arranged that the mixture to be extruded exhibits at least anaverage temperature (product temperature) corresponding to the softeningtemperature of component (C) and does not rise above a temperature atwhich the physiologically active substance (A) to be processed may bedamaged. Preferably, the temperature of the mixture to be extruded isadjusted to below 180° C., preferably below 150° C., but at least to thesoftening temperature of component (C).

After extrusion of the molten mixture and optional cooling of theextruded strand or extruded strands, the extrudates are preferablysingulated. This singulation may preferably be performed by cutting upthe extrudates by means of revolving or rotating knives, water jetcutters, wires, blades or with the assistance of laser cutters.

An inert gas atmosphere is not necessary for intermediate or finalstorage of the optionally singulated extrudate or the final shape of thedosage form according to the invention.

The singulated extrudate may be pelletised with conventional methods orbe press-formed into tablets in order to impart the final shape to thedosage form. It is, however, also possible not to singulate the extrudedstrands and, with the assistance of contrarotating calender rollscomprising opposing recesses in their outer sleeve, to form them intothe final shape, preferably a tablet, and to singulate these byconventional methods.

Should the optionally singulated extrudate not immediately be formedinto the final shape, but instead cooled for storage, after the periodof storage an inert gas atmosphere, preferably a nitrogen atmosphere,should be provided and must be maintained during heating of the storedextrudate up until plasticisation and definitive shaping to yield thedosage form.

The application of force in the extruder onto the at least plasticisedmixture is adjusted by controlling the rotational speed of the conveyingdevice in the extruder and the geometry thereof and by dimensioning theoutlet orifice in such a manner that the pressure necessary forextruding the plasticised mixture is built up in the extruder,preferably immediately prior to extrusion. The extrusion parameterswhich, for each particular composition, are necessary to give rise to adosage form with a resistance to crushing of at least 400 N, preferablyof at least 500 N, may be established by simple preliminary testing.

For example, extrusion may be performed by means of atwin-screw-extruder type Micro 27 GL 40 D (Leistritz, Nürnberg,Germany), screw diameter 18 mm. Screws having eccentric ends may beused. A heatable die with a round bore having a diameter of 8 mm may beused. The entire extrusion process should be performed under nitrogenatmosphere. The extrusion parameters may be adjusted e.g. to thefollowing values: rotational speed of the screws: 100 Upm; deliveryrate: 4 kg/h; product temperature: 125° C.; and jacket temperature: 120°C.

PROCESS EMBODIMENT 3

In this process variant for the production of the dosage form accordingto the invention energy is applied to a mixture of the components bymeans of ultrasonication.

First of all a homogeneous mixture of at least component (A) andcomponent (C) (=binder) is produced. Further auxiliary substances, suchas for example fillers, plasticisers, slip agents or dyes, may also beincorporated into this mixture. A low molecular weight polyethyleneglycol is preferably used as plasticiser.

Mixing may be performed with the assistance of conventional mixers.Examples of suitable mixers are roll mixers, which are also known astumbler, drum or rotary mixers, container mixers, barrel mixers (drumhoop mixers or tumbling mixers) or shaking mixers, shear mixers,compulsory mixers, plough bar mixers, planetary kneader-mixers, Zkneaders, sigma kneaders, fluid mixers or high-intensity mixers.

Selection of the suitable mixer is determined inter alia by theflowability and cohesiveness of the material to be mixed.

The mixture is then subjected to shaping. The mixture is preferablyshaped during or after ultrasonication, preferably by compaction.

It is particularly preferred during ultrasonication that there is directcontact between the mixture and the sonotrode of the ultrasound device.An ultrasound device as shown in FIG. 1 is preferably used in theprocess according to the invention.

In this FIG. 1, (1) denotes the press, with which the necessary force isapplied, (2) the converter, (3) the booster, (4) the sonotrode, (5) theshaping die, (6) the bottom punch, (7) the base plate, (8) and (9) theultrasound generator and device controller. The reference numerals usedrelate solely to FIG. 1.

A frequency of 1 kHz to 2 MHz, preferably of 15 to 40 kHz, should bemaintained during ultrasonication. Ultrasonication should be performeduntil softening of the polymer (C) is achieved. This is preferablyachieved within a few seconds, particularly preferably within 0.1 to 5seconds, preferably 0.5 to 3 seconds.

Ultrasonication and the application of force ensure uniform energytransfer, so bringing about rapid and homogeneous sintering of themixture. In this manner, dosage forms are obtained which have aresistance to crushing of at least 400 N, preferably of at least 500 N,and thus cannot be pulverised.

Before shaping is performed, the mixture may be granulated after themixing operation, after which the resultant granules are shaped into thedosage form with ultrasonication and application of force.

Granulation may be performed in machinery and apparatus known to theperson skilled in the art.

If granulation is performed as wet granulation, water or aqueoussolutions, such as for example ethanol/water or isopropanol/water, maybe used as the granulation liquid.

The mixture or the granules produced therefrom may also be subjected tomelt extrusion for further shaping, wherein the mixture is convertedinto a melt by ultrasonication and exposure to force and then extrudedthrough a dies. The strands or strand obtained in this manner may besingulated to the desired length using known apparatus. The formedarticles singulated in this manner may optionally furthermore beconverted into the final shape with ultrasonication and application offorce.

Final shaping to yield the dosage form preferably proceeds withapplication of force in appropriate moulds.

The above-described formed articles may also be produced with acalendering process by initially plasticising the mixture or thegranules produced therefrom by means of ultrasonication and applicationof force and performing extrusion through an appropriate die. Theseextrudates are then shaped into the final shape between twocontrarotating shaping rolls, preferably with application of force.

As already mentioned, shaping to yield the final shape of the dosageform by using a mixture comprising substance (A) and the polymer(C) witha resistance to crushing of at least 400 N, preferably of at least 500N, proceeds preferably in powder form by direct compression withapplication of force, wherein ultrasonication of this mixture isprovided before or during the application of force. The force is at mostthe force which is conventionally used for shaping dosage forms, such astablets, or for press-forming granules into the corresponding finalshape.

The tablets produced according to the invention may also be multilayertablets.

In multilayer tablets, at least the layer which contains substance (A)should be ultrasonicated and exposed to force.

The corresponding necessary application of force may also be applied tothe mixture with the assistance of extruder rolls or calender rolls.Shaping of the dosage forms preferably proceeds by direct press-formingof a pulverulent mixture of the components of the dosage form orcorresponding granules formed therefrom, wherein ultrasonicationpreferably proceeds during or before shaping. Such exposure continuesuntil the polymer (C) has softened, which is conventionally achieved inless than 1 second to at most 5 seconds.

A suitable press is e.g. a Branson WPS, 94-003-A, pneumatical (BransonUltraschall, Dietzenbach, Germany) having a plain press surface. Asuitable generator (2000 W) is e.g. a Branson PG-220A, 94-001-A analogue(Branson Ultraschall) with a sonotrode having a diameter of 12 mm. A diehaving a diameter of 12 mm may be used, the bottom of the die beingformed by a bottom punch having a plain press-surface and a diameter of12 mm. Suitable parameters for plastification are frequency: 20 kHz;amplitude: 50%; force: 250 N. The effect of ultrasound and force bymeans of the sonotrode may be maintained for e.g. 0.5 seconds, andpreferably both effects take place simultaneously.

PROCESS EMBODIMENT 4

In this process variant for the production of the dosage form accordingto the invention, components (A), (C), optionally present auxiliarysubstances (B), such as antioxidants, plasticisers and/ordelayed-release auxiliary substances, and optionally component (D), areprocessed with the assistance of a planetary-gear extruder to yield thedosage form according to the invention.

Planetary-gear extruders are known and described inter alia in detail inHandbuch der Kunststoff-Extrusionstechnik I (1989) “Grundlagen” inChapter 1.2 “Klassifizierung von Extrudern”, pages 4 to 6. Thecorresponding description is hereby introduced as a reference and isdeemed to be part of the disclosure.

Below, the use of a planetary-gear extruder in the process according tothe invention is explained with reference to FIGS. 2 and 3. Theseexplanations are given merely by way of example and do not restrict thegeneral concept of the invention.

FIG. 2 shows a section through a planetary-gear extruder and

FIG. 3 shows the mode of operation of the planetary-gear extruder.

FIG. 2 shows a planetary-gear extruder which may be used in the processaccording to the invention. This extruder substantially comprises ashaft 1, which, relative to the transport direction of the mixture ofthe components listed above to be extruded, is initially constructed asa feed screw 5 and subsequently as the central spindle 3 of theplanetary-gear extruder. Around the central spindle 3 there arepreferably arranged three to seven planetary spindles 4, which are inturn surrounded by a casing in the form of a housing 6.

In the planetary-gear extruder, extrusion of the composition used in theprocess according to the invention for the production of apharmaceutical dosage form preferably proceeds as follows, withreference to FIG. 2. As shown by arrow 2, the components to be extrudedare apportioned by the apportioning unit 7 in the area of the feed screw5 and conveyed by the rotation thereof (drive not shown) in thedirection of the central spindle 3. The person skilled in the art willunderstand that it is possible to mix the starting materials(components) in the area of the feed screw. However, it is also possibleto premix the components of the dosage form and to apportion thismixture via the apportioning unit 7 in the area of the feed screw 5. Themixture is conveyed into the feed zone of the planetary-gear extruder.By heating at least to the softening point of component (C), the mixtureis melted and the molten mixture is conveyed into the area of thecentral spindle, i.e. the extrusion zone, by the interaction of thecentral spindle 3 and the planetary spindles 4, further homogenised,compressed or compacted and extruded through the die 8 as an extrudedstrand or extruded strands, depending on how many bores the diecomprises. The die geometry or the geometry of the bores is freelyselectable. Thus, the die or the bores may exhibit a round, oblong oroval cross-section, wherein the round cross-section preferably has adiameter of 0.1 mm to 15 mm and the oblong cross-section preferably hasa maximum lengthwise extension of 21 mm and a crosswise extension of 10mm. The extrusion die may also take the form of a slot die. Preferably,the die or the bores have a round, oval or oblong cross-section. Boththe casing 6 of the planetary-gear extruder used according to theinvention and the central spindle may be heated or cooled. Thecorresponding temperature control, i.e. heating or cooling, is soarranged that the mixture to be extruded exhibits an average temperaturecorresponding to the softening temperature of component (C) and does notrise above a temperature at which the substance (A) to be processed maybe damaged. Preferably, the temperature of the mixture to be extruded isadjusted to below 180° C., preferably below 150° C., but at least to thesoftening temperature of component (C). The reference numerals usedrelate solely to FIGS. 2 and 3.

After extrusion of the molten mixture and optional cooling of theextruded strand or extruded strands, the extrudates are singulated (notshown in FIG. 2). This singulation may preferably be performed bycutting up the extrudates by means of revolving or rotating knives,water jet cutters, wires, blades or with the assistance of lasercutters.

Optionally after further cooling of the singulated extrudates, which arepreferably present in the form of disks, they are optionally re-shapedinto the final shape of the dosage form, wherein they may be exposed toheat again if necessary.

This shaping for example into tablets may proceed in that the plasticextrudate is shaped with press-forming with the assistance of twocontrarotating rolls preferably with mutually opposing recesses forplastification in the roll sleeve, the construction of which recessesdetermines the tablet shape.

However, it is also possible to form the tablets from the singulatedextrudates in each case with the assistance of an optionally heated dieand at least one shaping punch. To this end, the cylindrical granulesobtained after singulation of the extruded strand may preferably beused. Apart from being press-formed into tablets, these granules orother multiparticulate shapes obtained, such as pellets or spheroids,may also be packaged into capsules in order to be used as a dosage formproduced according to the invention.

In a further preferred embodiment, the extruded strands extruded througha plurality of bores in the extrusion die may, after cooling thereof,optionally be brought together by interlacing or wrapping in the mannerof rope production to yield a thicker strand than the individualextruded strands. This strand may optionally be further processed bysolvent attack with a suitable solvent or by heating to the softeningpoint of the polymer (C) and optionally removing the solvent inaccordance with the above-stated singulation and shaping of anindividual strand.

FIG. 3 shows a cross-section through the planetary-gear extruder. Aroundthe rotating central spindle 3 there are arranged at least three, in thecase illustrated 6, planetary spindles 4, whose flanks 41 interact onthe one hand with the flank 31 of the central spindle 4 and on the otherhand with the flanks 61 of the casing 6 of the planetary-gear extruder.Through rotation of the central spindle 3 and rolling of the respectiveflanks over one another, the planetary spindles 4 each rotate aroundtheir own axis, as shown by arrow 42, and around the central spindle 4,as shown by arrow 43. In this way, the compression or compaction soughtaccording to the invention of the component mixture used according tothe invention of the dosage forms produced according to the invention isachieved. The reference numerals used relate solely to FIGS. 2 and 3.

If necessary, the planetary-gear extruder used may comprise not only anextrusion zone but also at least one further zone, so that the mixtureto be extruded may optionally also be degassed.

The process according to the invention may be performed discontinuouslyor continuously, preferably continuously.

A suitable extruder, for example, is a planetary gear extruder type BCG10 (LBB Bohle, Ennigerloh, Germany) having four planetary spindles andan extrusion die with bores having a diameter of 8 mm. A gravimetricaldosing of 3.0 kg/h is suitable. The extrusion may be performed, forexample, at a rotational speed of 28.6 rmp and a product temperature ofabout 88° C.

PROCESS EMBODIMENT 5

This variant for the production of the dosage form according to theinvention is performed by processing at least the components (A), (C),optionally present auxiliary substances (B), such as antioxidants,plasticisers and/or delayed-release auxiliary substances, and optionallycomponent (D), with addition of a solvent for component (C), i.e. forthe polymer or polymers (C), to yield the dosage form.

To this end, components (A), (C), optionally (B) and the optionallypresent component (D) are mixed and, after addition of the solvent andoptionally after granulation, the resultant formulation mixture isshaped to yield the dosage form.

Components (A), (C), optionally (B) and optionally (D) are mixed in amixer known to the person skilled in the art. The mixer may, forexample, be a roll mixer, shaking mixer, shear mixer or compulsorymixer.

The solvent for the polymer (C) is added at least in such quantitiesthat the formulation mixture is uniformly moistened.

Solvents which are suitable for the polymer (C) are preferably aqueoussolvents, such as water, mixtures of water and aliphatic alcohols,preferably C1 to C6 alcohols, esters, ethers, hydrocarbons, particularlypreferably distilled water, short-chain alcohols, such as methanol,ethanol, isopropanol, butanol or aqueous alcohol solutions.

The solvent is preferably added with stirring. The uniformly moistenedcomposition is then dried. Drying preferably proceeds with exposure toheat at temperatures at which it is possible to rule out anydiscoloration of the composition. This temperature may be established bysimple preliminary testing.

Before or after drying, the composition may be divided into sub-portionswhich preferably in each case correspond to the mass of a unit of thedosage form. The corresponding dried portions are then shaped to yieldthe dosage form.

This is preferably achieved by using tablet presses.

The formulation mixture may also be moistened in such a manner that,before addition of the solvent, the formulation mixture is divided,preferably in moulds, into sub-portions, is dispersed in a liquiddispersant with stirring and then the solvent is added. Component (C) isnot soluble in the dispersant, which must be miscible with the solvent.

Suitable dispersants are preferably hydrophilic solvents, such asaliphatic alcohols, ketones, esters. Short-chain alcohols are preferablyused.

Alternatively, the formulation mixture may also be moistened in such amanner that the solvent is incorporated into the formulation mixture asa foam. Such a foam of the solvent is preferably produced with theassistance of a high-speed mixer, preferably with the addition ofconventional foam stabilisers. Suitable stabilisers are, for example,hydrophilic polymers such as for example hydroxypropylmethylcellulose.

The foam is also preferably incorporated into the formulation mixturewith stirring, a granulated composition so preferably being obtained.

Before or after being divided into sub-portions, which preferablycorrespond to the mass of a unit of the dosage form, the granulatedcomposition is dried and then shaped into the dosage form.

Drying and shaping may preferably proceed as described above. Theprocess according to the invention may also be performed in such amanner that solvent is added to the formulation mixture in such aquantity that a shapeable paste is obtained.

Before or after being dried, which may proceed as explained above, sucha paste may be divided into sub-portions and the dried portions, afterfurther division in each case into a portion corresponding to the massof a unit of the dosage form, are shaped or converted to yield thedosage form.

It is here possible to form the sub-portions in the form of strands,which may be produced with the assistance of a screen or a strandformer. The dried strands are preferably singulated and shaped to yieldthe dosage form. This shaping preferably proceeds with the assistance ofa tablet press, using shaping rollers or shaping belts equipped withrollers.

It is also possible to convert the paste into a planar structure and tostamp the dosage form out of it once it has dried.

The paste is advantageously processed with an extruder, wherein,depending on the configuration of the extrusion, strands or planarstructures articles are produced, which are singulated by chopping,cutting or stamping. The singulated sub-portions may be shaped, formedor stamped as described above to yield the dosage form. Correspondingapparatuses are known to the person skilled in the art.

The process according to the invention may here be performedcontinuously or discontinuously.

It is also possible to add solvent to the formulation mixture in such aquantity that at least the polymer component (C) is dissolved. Such asolution or dispersion/suspension is preferably converted into a planarstructure, an extruder with a flat die preferably being used or thesolution being cast onto a planar support.

As stated above, after drying, the dosage forms may be obtained from theplanar structures by stamping or calendering. It is also possible, asstated above, to convert the solution into strands and to singulatethese, preferably after they have been dried, and shape them to yieldthe dosage form.

Alternatively, the solution may also be divided into portions such that,after drying, they each correspond to the mass of a unit of the dosageform, with moulds which already correspond to the shape of the unit ofthe dosage form preferably being used for this purpose.

If the solution is divided into any desired portions, the portions may,after drying, optionally be combined again and be shaped to form thedosage form, being for example packaged in a capsule or press-formed toform a tablet.

The formulation mixtures combined with solvent are preferably processedat temperatures of 20° C. to 40° C., wherein, apart from during dryingto remove the solvent and the optionally present dispersant, no highertemperatures are used. The drying temperature must be selected below thedecomposition temperature of the components. After shaping to yield thedosage form, further drying corresponding to the above-described dryingmay optionally be performed.

Combinations of individual process steps of the above process variantsare also possible in order to produce the dosage form according to theinvention.

Process variants 2 and 4 as described above involve the extrusion of acomposition comprising components (A), (C), optionally (B) andoptionally (D). Preferably, extrusion is performed by means oftwin-screw-extruders or planetary-gear-extruders, twin-screw extrudersbeing particularly preferred.

Morphology

It has been surprisingly found that extrudates exhibiting anadvantageous morphology are obtainable by means ofplanetary-gear-extruders and twin-screw-extruders. It has been foundthat under suitable conditions the extrudate is surrounded by a shellwhich may be denoted as “extrusion skin”. Said extrusion skin can beregarded as a collar-like or tubular structure forming a circumferentialsection of the extrudate about its longitudinal extrusion axis so thatthe outer surface of said collar-like or tubular structure forms theclosed shell of the extrudate. Usually, only the front faces of theextrudate are not covered by said extrusion skin.

The extrusion skin surrounds the core of the extrudate in a collar-likeor tubular arrangement and preferably is connected therewith in aseamless manner. The extrusion skin differs from said core in itsmorphology. Usually, the extrusion skin is visible with the naked eye inthe cross-section of the extrudate, optionally by means of a microscope,since due to the different morphology of the material forming theextrusion skin and the material forming the core, the optical propertiesdiffer as well. It seems that during extrusion the material forming theextrusion skin is exposed to mechanical and thermal conditions differingfrom the conditions the core of the extrudate is exposed to. Inconsequence, a heterogeneous morphology of the extruded strand isobtained, which e.g. assumes radial symmetry when an extrusion diehaving circular shape is used. The material forming the extrusion skinand the material forming the core are usually distinguished by theirmorphology, preferably, however, not by their composition, particularlynot by the relative content of components (A), (C), optionally (B) andoptionally (D).

Usually the extrusion skin covers the entire shell of the extrudate likea one-piece collar, independently of what geometry has been chosen forthe extrusion die. Therefore, the extrudate may assume circular,elliptic or other cross-sections.

The extrusion skin is preferably characterized by a unitary thickness.Preferably, the thickness of the extrusion skin is within the range from0.1 to 4.0 mm, or, in increasing order of preference 0.15 to 3.5 mm, 0.2to 3.0 mm, 0.2 to 2.5 mm or 0.2 to 2.0 mm. In a preferred embodiment thethickness of the extrusion skin in the sum over both opposing sidesamounts to 0.5 to 50%, or in increasing order of preference 1.0 to 40%,1.5 to 35%, 2.0 to 30% or 2.5 to 25% of the diameter of the extrudate.

FIG. 4 shows a schematic view of extrudate (71) having a collar-likeextrusion skin (72) entirely surrounding the core (73) about thelongitudinal extrusion axis (74). The outer surface of extrusion skin(72) forms the shell (75) of the extrudate (71).

It has been surprisingly found that extrudates having an extrusion skinexhibit beneficial mechanical properties. They are particularly suitableas intermediates in the production of the dosage forms according to theinvention, because they may be advantageously processed, in particularby singulating and/or forming.

When the dosage forms according to the invention are prepared by meansof extrusion processes which lead to intermediates having an extrusionskin as described above, the dosage forms obtained therefrom arepreferably also characterized by a particular morphology.

In a preferred embodiment those regions, which have formed the extrusionskin in the extruded intermediate, are still visible with the naked eye,optionally by means of a microscope, in the cross-section of the dosageform. This is because usually by further processing the extrudate,particularly by singulating and/or shaping, the different nature andthereby also the different optical properties of the material formingthe extrusion skin and the material forming the core are maintained. Inthe following, that domain of the dosage forms which has emerged fromthe extrusion skin in the course of further processing the extrudedintermediate, will be denoted as “tubular domain”.

Preferably, the dosage form according to the invention comprises atubular domain and a core located therein. Preferably, the tubulardomain is connected with the core in a seamless manner. Preferably thetubular domain as well as the core have substantially the same chemicalcomposition, i.e. substantially the same relative content of components(A), (C), optionally (B) and optionally (D). The material forming thetubular domain has a morphology differing from the material forming thecore. Usually, this different morphology is also expressed in terms ofdifferent optical properties, so that the tubular domain and the coreare visible with the naked eye in the cross-section of the dosage form.

In case that the dosage form has been coated, e.g. by a film coating,the tubular domain is located between the film coating and the core.Since the dosage form according to the invention may be obtained indifferent ways from the extrudate containing the extrusion skin(intermediate), the tubular domain may take different arrangements andextensions within the dosage form according to the invention. Allarrangements have in common, however, that the tubular domain partiallycovers the surface of the core, but usually not its entire surface.Preferably, two opposing surfaces of the core are not, or at least notfully covered by the tubular domain. In other words, preferably thetubular domain has two openings/blanks on opposing sides.

The thickness of the tubular domain may be uniform. It is also possible,however, that in the course of the processing, i.e. due to thesubsequent shaping (e.g. press-forming) of the extrudate, varioussections of the extrusion skin are expanded or compressed differentlythereby leading to a variation of the thickness of the tubular domainwithin the dosage form.

Preferably the thickness of the tubular domain is within the range from0.1 to 4.0 mm, or in increasing order of preference 0.15 to 3.5 mm, 0.2to 3.0 mm, 0.2 to 2.5 mm or 0.2 to 2.0 mm.

FIGS. 5A and 5B show schematic views of preferred arrangements of thetubular domain within the dosage form according to the invention. Thedosage forms (81) contain a tubular domain (82) partially surroundingthe core (83). The opposing surfaces (84 a) and (84 b) of the core (83),however, are not covered by the tubular domain (82).

The process for the preparation of the dosage form according to theinvention is preferably performed continuously. Preferably, the processinvolves the extrusion of a homogeneous mixture of components (A), (C),optionally (B) and optionally (D). It is particularly advantageous ifthe obtained intermediate, e.g. the strand obtained by extrusion,exhibits uniform properties. Particularly desirable are uniform density,uniform distribution of the active substance, uniform mechanicalproperties, uniform porosity, uniform appearance of the surface, etc.Only under these circumstances the uniformity of the pharmacologicalproperties, such as the stability of the release profile, may be ensuredand the amount of rejects can be kept low.

Preferably, the process according to the present invention may beperformed with less than 25% rejects, more preferably less than 20%,most preferably less than 15% and in particular less than 10% rejects,wherein the criteria for rejection are the FDA standards regarding theintervariability of the content of component (A), its release profileand/or the density of the dosage form when comparing two dosage forms,preferably taken from the same batch.

It has been surprisingly found that the above properties may be obtainedby means of twin-screw-extruders and planetary-gear-extruders,twin-screw-extruders being particularly preferred.

The process according to the invention preferably involves the extrusionof a mixture of components (A), (C), optionally (B) and optionally (D),preferably by means of a planetary-gear-extruder or atwin-screw-extruder. After extrusion the extrudate is preferablysingulated, shaped and optionally coated in order to obtain the finaldosage form.

In a preferred embodiment of the process according to the invention,shaping is performed in the plasticized state of the mixture ofcomponents (A), (C), optionally (B) and optionally (D). It has beensurprisingly found that the extrusion of certain polymers (C),particular of high molecular weight polyethylene oxides, yieldsintermediates exhibiting some kind of memory effect: when the singulatedextrudates are shaped at ambient temperature, e.g. by press-forming,dosage forms are obtained which tend to regain their original outer formupon storage under stressed storage conditions, i.e. they return to theform they had prior to shaping.

The shape of the dosage form upon storage at stressed conditions, e.g.at 40° C. and 75% RH, may also be unstable for other reasons.

The memory effect significantly deteriorates the storage stability ofthe dosage form, as by regaining its outer form several properties ofthe dosage form are changed. The same applies to any changes of theouter form due to other reasons.

It has been found that, for example, depending on the extrusionconditions a significant expansion of the strand may occur therebyresulting in an increase of the volume of the extrudate, i.e. a decreaseof its density. Such expansion may be compensated by subsequentlypress-forming the singulated extrudate at a sufficient pressure, sinceunder these conditions the expansion of the material may be reversed.

However, if press-forming has been performed at ambient temperature, thememory effect of the compressed extrudate will cause it to swell and toexpand upon storage, thereby significantly increasing the volume of thedosage form.

It has been surprisingly found that such memory effect may be suppressedif shaping of the singulated extrudate is performed at increasedtemperature, i.e. in the plasticized state of the mixture of components(A), (C), optionally (B) and optionally (D). Preferably, shaping isperformed at a pressure of at least 1 kN, more preferably within therange from 2 kN to 50 kN, e.g. by means of a tablet press. Preferably,shaping is performed at a temperature which preferably is about 40° C.,more preferably about 30° C. and in particular about 25° C. below themelting range of the mixture of components (A), (C), optionally (B) andoptionally (D). The melting range of a given mixture may be determinedby conventional methods, preferably by DSC (e.g. with a DSC model 2920(TA Instruments, New Castle) and ultrahigh pure nitrogen as purge gas ata flow rate of 150 ml/min; approximate sample weight of 10-20 mg, sealedin nonhermetic aluminium pans; temperature ramp speed 10° C./min).

In a preferred embodiment the outer shape of the dosage form accordingto the invention does not substantially change when being stored for atleast 12 h, preferably for at least 24 h, at 40° C. and 75% RH,preferably in an open container.

In a preferred embodiment the volume of the dosage form according to theinvention increases by not more than 20% or 17.5%, more preferably notmore than 15% or 12.5%, still more preferably not more than 10% or 7.5%,most preferably not more than 6.0%, 5.0% or 4.0% and in particular notmore than 3.0%, 2.0% or 1.0% when being stored for at least 12 h,preferably for at least 24 h, at a temperature of 20° C. below themelting range of the mixture of components (A), (C), optionally (B) andoptionally (D), optionally at a temperature of 40° C. and 75% RH.

The dosage form according to the invention exhibits controlled releaseof the active ingredient. It is preferably suitable for twice dailyadministration to patients.

The dosage form according to the invention may comprise one or moresubstances (A) at least in part in a further delayed-release form,wherein delayed release may be achieved with the assistance ofconventional materials and processes known to the person skilled in theart, for example by embedding the substance in a delayed-release matrixor by applying one or more delayed-release coatings. Substance releasemust, however, be controlled such that addition of delayed-releasematerials does not impair the necessary hardness.

Controlled release from the dosage form according to the invention ispreferably achieved by embedding the substance in a matrix. Theauxiliary substances acting as matrix materials control release. Matrixmaterials may, for example, be hydrophilic, gel-forming materials, fromwhich release proceeds mainly by diffusion, or hydrophobic materials,from which release proceeds mainly by diffusion from the pores in thematrix.

Physiologically acceptable, hydrophobic materials which are known to theperson skilled in the art may be used as matrix materials. Polymers,particularly preferably cellulose ethers, cellulose esters and/oracrylic resins are preferably used as hydrophilic matrix materials.Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivativesthereof, such as the salts, amides or esters thereof are veryparticularly preferably used as matrix materials.

Matrix materials prepared from hydrophobic materials, such ashydrophobic polymers, waxes, fats, long-chain fatty acids, fattyalcohols or corresponding esters or ethers or mixtures thereof are alsopreferred. Mono- or diglycerides of C12-C30 fatty acids and/or C12-C30fatty alcohols and/or waxes or mixtures thereof are particularlypreferably used as hydrophobic materials.

It is also possible to use mixtures of the above-stated hydrophilic andhydrophobic materials as matrix materials.

Component (C) and the optionally present component (D), which serve toachieve the resistance to crushing of at least 400 N which is necessaryaccording to the invention, may furthermore themselves serve asadditional matrix materials.

If the dosage form according to the invention is intended for oraladministration, it may also preferably comprise a coating which isresistant to gastric juices and dissolves as a function of the pH valueof the release environment. By means of this coating, it is possible toensure that the dosage form according to the invention passes throughthe stomach undissolved and the active ingredient is only released inthe intestines. The coating which is resistant to gastric juicespreferably dissolves at a pH value of between 5 and 7.5.

Corresponding materials and methods for the delayed release of activeingredients and for the application of coatings which are resistant togastric juices are known to the person skilled in the art, for examplefrom “Coated Pharmaceutical Dosage Forms—Fundamentals, ManufacturingTechniques, Biopharmaceutical Aspects, Test Methods and Raw Materials”by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart,1st edition, 1998, Medpharm Scientific Publishers. The correspondingliterature description is hereby introduced as a reference and is deemedto be part of the disclosure.

The invention also relates to the use of a physiologically activesubstance (A) as described above and/or a synthetic or natural polymer(C) as described above for the manufacture of the dosage form accordingto the invention for the prophylaxis and/or the treatment of a disorder,thereby preventing an overdose of the physiologically active substance(A), particularly due to comminution of the dosage form by mechanicalaction.

Further, the invention relates to a method for the prophylaxis and/orthe treatment of a disorder comprising the administration of the dosageform according to the invention, thereby preventing an overdose of thephysiologically active substance (A), particularly due to comminution ofthe dosage form by mechanical action.

Preferably, the mechanical action is selected from the group consistingof chewing, grinding in a mortar, pounding, and using apparatuses forpulverising conventional dosage forms.

The resistance to crushing of the dosage forms obtained according to theinvention is determined by the stated measurement method, with dosageforms other than tablets also being tested.

The resistance to crushing of the dosage form according to the inventionmay be determined by producing dosage forms, preferably tablets, with adiameter of 10 mm and a height of 5 mm.

Using these dosage forms, preferably tablets, the resistance to crushingof the dosage form is determined in accordance with the method fordetermining the resistance to crushing of tablets, published in theEuropean Pharmacopoeia 1997, page 143, 144, method no. 2.9.8. using theapparatus stated below. The apparatus used for the measurement is a“Zwick Z 2.5” materials tester, Fmax=2.5 kN with a maximum draw of 1150mm, which should be set up with 1 column and 1 spindle, a clearancebehind of 100 mm and a test speed adjustable between 0.1 and 800 mm/mintogether with testControl software. Measurement is performed using apressure piston with screw-in inserts and a cylinder (diam. 10 mm), aforce transducer, Fmax. 1 kN, diameter=8 mm, class 0.5 from 10 N, class1 from 2 N to ISO 7500-1, with manufacturer's test certificate M to DIN55350-18 (Zwick gross force Fmax=1.45 kN) (all apparatus from Zwick GmbH& Co. KG, Ulm, Germany) with order no. BTC-FR 2.5 TH. D09 for thetester, order no. BTC-LC 0050N. P01 for the force transducer, order no.BO 70000 S06 for the centring device.

FIG. 6 shows the measurement of the resistance to crushing of a tablet,in particular the tablet (4) adjustment device (6) used for this purposebefore and during the measurement. To this end, the tablet (4) is heldbetween the upper pressure plate (1) and the lower pressure plate (3) ofthe force application apparatus (not shown) with the assistance of two2-part clamping devices, which are in each case firmly fastened (notshown) with the upper and lower pressure plate once the spacing (5)necessary for accommodating and centring the tablet to be measured hasbeen established. The spacing (5) may be established by moving the2-part clamping devices horizontally outwards or inwards in each case onthe pressure plate on which they are mounted. The reference numeralsused relate solely to FIG. 6.

In case that the dosage form according to the invention is inmultiparticulate form, the resistance to crushing may be alternativelybe determined by means of two pressure plates, such as depicted e.g. inFIG. 7.

FIG. 7 shows a probe (12), e.g. a pellet, which is placed between a toppressure plate (10) and a bottom pressure plate (11). Force is effectedto the probe by means of the two pressure plates. The result of themeasurement is analysed analogously to the method that has beendescribed above in connection with FIG. 6.

The tablets deemed to be resistant to crushing under a specific loadinclude not only those which have not broken but also those which mayhave suffered plastic deformation under the action of the force.

The invention is explained below with reference to Examples. Theseexplanations are given merely by way of example and do not restrict thegeneral concept of the invention.

In a first series of examples diltiazem hydrochloride, verapamilhydrochloride and carbamazepine were used as the active ingredients(substance (A)):

EXAMPLE 1

per Complete Components tablet batch diltiazem HCl  90.0 mg   720 mgpolyethylene oxide, NF, MW 7 000 000 154.2 mg 1233.6 mg (Polyox WSR 303,Dow Chemicals) total weight 244.2 mg 1.9536 g  

All the components were mixed in a free-fall mixer. A tabletting toolwith top punch, bottom punch and die for tablets with a diameter of 10mm and a radius of curvature (concavity) of 8 mm was heated to 80° C. ina heating cabinet. Portions of the powder mixture were pressed with theheated tool, wherein pressure was maintained for at least 15 seconds byclamping the tabletting tool in a vice.

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. This could not be achieved with the assistanceof a pestle and mortar either.

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus in accordance with Pharm. Eur.(paddle with sinker). The temperature of the release medium was 37° C.and the rotational speed of the stirrer 50 min⁻¹. At the beginning ofthe investigation, each tablet was placed in a 900 ml portion ofartificial gastric juice, pH 1.2. After 30 minutes, the pH value wasincreased to 2.3 by addition of alkali solution, after a further 90minutes to pH 6.5 and after a further 60 minutes to pH 7.2. The quantityof active ingredient released in each case into the dissolution mediumat any one time was determined by spectrophotometry at 236 nm in 2 mmmeasurement cells. time released quantity  30 min 12% 240 min 43% 480min 63% 600 min 71% 720 min 77%

EXAMPLE 2

In a manner similar to Example 1, oblong tablets having a width of 9 mmand a lengthwise extension of 20 mm were produced with the followingcomposition: per complete Components tablet batch verapamil HCl 240.0 mg  1920 mg polyethylene oxide, NF, MW 7 000 000 411.4 mg 3291.2 mg(Polyox WSR 303, Dow Chemicals) total weight 651.4 mg 4.2112 g  

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N.

In vitro release of the active ingredient was determined in a mannersimilar to Example 1 (UV detector at 279 nm) and was: Time releasedquantity  30 min  6% 240 min 20% 480 min 30% 600 min 35% 720 min 39%

EXAMPLE 3

In a similar manner to Example 1, round tablets with a diameter of 20 mmand of the following composition were produced: per complete Componentstablet batch Carbamazepine   600 mg   4800 mg polyethylene oxide, NF, MW7 000 000 1028.5 mg 8228.0 mg (Polyox WSR 303, Dow Chemicals) totalweight 1628.5 mg 13.028 g  

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N.

In vitro release of the active ingredient was determined in a mannersimilar to Example 1 (UV detector at 285 nm) and was: time releasedquantity  30 min 1% 240 min 5% 480 min 9% 600 min 11%  720 min 13% 

In a further series of examples nifedipine was used as the activeingredient (substance (A)):

EXAMPLE 4

Tablets having the following composition were produced: per completecontent components tablet batch [%] nifedipine 20 mg 2 g 10 polyethyleneoxide 900 000 180 mg  18 g  90 (Polyox WSR 1105 Dow Chemicals)

Nifedipine and polyethylene oxide were mixed in a free-fall mixer. Themixture was compressed on an excentric tablet press (model EK 0, Korsch)to circular tablets having a weight of 200 mg, a diameter of 8 mm and aradius of curvature of 8 mm. Then, the tabletting tool with top punch,bottom punch and die for tablets with a diameter of 10 mm and a radiusof curvature of 8 mm was heated to 100° C. in a heating cabinet. Onceagain the tablets were compressed by means of the heated tool, whereinpressure was maintained for at least 15 seconds.

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. This could not be achieved with the assistanceof a pestle and mortar either.

EXAMPLE 5

Tablets having the following composition were produced as described inExample 4: per complete content Components tablet batch [%] Nifedipine20 mg 2 g 10 polyethylene oxide 600 000 180 mg  18 g  90 (Polyox WSR 205Dow Chemicals)

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. This could not be achieved with the assistanceof a pestle and mortar either.

EXAMPLE 6

Tablets having the following composition were produced as described inExample 4: per complete content Components tablet batch [%] Nifedipine20 mg 2 g 10 polyethylene oxide 5 000 000 180 mg  18 g  90 (Polyox WSRCoagulant Dow Chemicals)

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. This could not be achieved with the assistanceof a pestle and mortar either.

EXAMPLE 7

Tablets having the following composition were produced as described inExample 4: per complete content Components tablet batch [%] Nifedipine20 mg 2 g 10 polyethylene oxide 100 000 20 mg 2 g 10 (Polyox WSR N 10Dow Chemicals) polyethylene oxide 5 000 000 160 mg  160 g  80 (PolyoxWSR Coagulant Dow Chemicals)

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. This could not be achieved with the assistanceof a pestle and mortar either.

In a further series of examples tramadol hydrochloride and oxycodonehydrochloride were used as active ingredients (substance (A)).

EXAMPLE 8

per complete Components tablet batch tramadol HCl 100 mg 100 gpolyethylene oxide, NF, MFI 200 mg 200 g (190° C. at 21.6 kg/10 min)<0.5 g MW 7 000 000 (Polyox WSR 303, Dow Chemicals) total weight 300 mg300 g

Tramadol hydrochloride and polyethylene oxide powder were mixed in afree-fall mixer. A tabletting tool with top punch, bottom punch and diefor tablets with a diameter of 10 mm and a radius of curvature of 8 mmwas heated to 80° C. in a heating cabinet. 300 mg portions of the powdermixture were pressed with the heated tool, wherein pressure wasmaintained for at least 15 seconds by clamping the tabletting tool in avice.

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notbreak when exposed to a force of 500 N.

The tablet could not be comminuted using a hammer, nor with theassistance of a mortar and pestle.

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus in accordance with Pharm. Eur.The temperature of the release medium was 37° C. and the rotationalspeed of the stirrer 75 min⁻¹. At the beginning of the investigation,each tablet was placed in a 600 ml portion of artificial gastric juice,pH 1.2. After 30 minutes, the pH value was increased to 2.3 by additionof alkali solution, after a further 90 minutes to pH 6.5 and after afurther 60 minutes to pH 7.2. The released quantity of active ingredientpresent in the dissolution medium at each point in time was determinedby spectrophotometry. time released quantity  30 min 15% 240 min 52% 480min 80% 720 min 99%

EXAMPLE 9

300 mg portions of the powder mixture from Example 8 were heated to 80°C. and in placed in the die of the tabletting tool. Pressing was thenperformed. The tablet exhibits the same properties such as the tablet inExample 8.

EXAMPLE 10

per complete Components tablet batch tramadol HCl  50 mg 100 gpolyethylene oxide, NF, MW 7 000 000 100 mg 200 g (Polyox WSR 303, DowChemicals) total weight 150 mg 300 g

Tramadol hydrochloride and the above-stated components were mixed in afree-fall mixer. A tabletting tool with top punch, bottom punch and diefor tablets with a diameter of 7 mm was heated to 80° C. in a heatingcabinet. 150 mg portions of the powder mixture were pressed with theheated tool, wherein pressure was maintained for at least 15 seconds byclamping the tabletting tool in a vice.

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notbreak when exposed to a force of 500 N.

In vitro release of the active ingredient was determined as in Example 8and was: time released quantity  30 min 15% 240 min 62% 480 min 88% 720min 99%

EXAMPLE 11

per complete Components tablet batch tramadol HCl 100 mg 100 gpolyethylene oxide, NF, MW 7 000 000 180 mg 180 g (Polyox WSR 303, DowChemicals) Xanthan, NF  20 mg  20 g total weight 300 mg 300 g

Tramadol hydrochloride, xanthan and polyethylene oxide were mixed in afree-fall mixer. A tabletting tool with top punch, bottom punch and diefor tablets with a diameter of 10 mm and a radius of curvature(concavity) of 8 mm was heated to 80° C. in a heating cabinet. 300 mgportions of the powder mixture were pressed with the heated tool,wherein pressure was maintained for at least 15 seconds by clamping thetabletting tool in a vice.

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notbreak when exposed to a force of 500 N. The tablets did suffer a littleplastic deformation.

In vitro release of the active ingredient was determined as in Example 8and was: time released quantity  30 min 14% 240 min 54% 480 min 81% 720min 99%

EXAMPLE 12

per complete Components tablet batch tramadol HCl 50 mg 100 gpolyethylene oxide, NF, MW 7 000 000 90 mg 180 g (Polyox WSR 303, DowChemicals) Xanthan, NF 10 mg  20 g total weight 300 mg  300 g

Tramadol hydrochloride, xanthan and polyethylene oxide were mixed in afree-fall mixer. A tabletting tool with a top punch, bottom punch anddie for oblong tablets 10 mm in length and 5 mm in width was heated to90° C. in a heating cabinet. 150 mg portions of the powder mixture werepressed with the heated tool, wherein pressure was maintained for atleast 15 seconds by clamping the tabletting tool in a vice.

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notbreak when exposed to a force of 500 N. The tablets did suffer a littleplastic deformation.

In vitro release of the active ingredient was determined as in Example 8and was: time released quantity  30 min 22% 120 min 50% 240 min 80% 360min 90% 480 min 99%

EXAMPLE 13

A tablet with the following composition was produced as described inExample 8: per per Components tablet batch oxycodone HCl  20.0 mg 0.240g Xanthan, NF  20.0 mg 0.240 g polyethylene oxide, NF, MFI 110.0 mg1.320 g (190° C. at 21.6 kg/10 min) <0.5 g MW 7 000 000 (Polyox WSR 303,Dow Chemicals) total weight 150.0 mg 1.800 g

Release of the active ingredient was determined as follows:

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus in accordance with Pharm. Eur.The temperature of the release medium was 37° C. and the rotationalspeed 75 rpm. The phosphate buffer, pH 6.8, described in DSP served asthe release medium. The quantity of active ingredient present in thesolvent at the particular time of testing was determined byspectrophotometry. Time mean  0 min 0%  30 min 17% 240 min 61% 480 min90% 720 min 101.1%

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notbreak when exposed to a force of 500 N.

EXAMPLE 14

Tablets having the following composition were produced: per completecontent components tablet batch [%] tramadol HCl 100 mg  10 g 20polyethylene oxide 7 000 000 375 mg 37.5 g  75 (Polyox WSR 303, DowChemicals) Carnauba wax  25 mg 2.5 g 5.0

Tramadol hydrochloride polyethylene oxide and Carnauba wax were mixed ina free-fall mixer. The mixture was compressed on an excentric tabletpress (model EK 0, Korsch) to circular tablets having a weight of 500mg, a diameter of 10 mm and a radius of curvature of 8 mm. Then, thetabletting tool with top punch, bottom punch and die for tablets with adiameter of 10 mm and a radius of curvature of 8 mm was heated to 130°C. in a heating cabinet. Once again the tablets were compressed by meansof the heated tool, wherein pressure was maintained for at least 15seconds.

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. This could not be achieved with the assistanceof a pestle and mortar either.

EXAMPLE 15

Tablets having the following composition were produced as described inExample 14: per complete content Components tablet batch [%] tramadolHCl 100 mg  10 g 20 polyethylene oxide 5 000 000 375 mg 37.5 g  75(Polyox WSR Coagulant Dow Chemicals) Carnauba wax  25 mg 2.5 g 5.0

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. This could not be achieved with the assistanceof a pestle and mortar either.

EXAMPLE 16

Tablets having the following composition were produced: per completecontent Components tablet batch [%] tramadol HCl 100.0 mg  1490 g  29.8polyethylene oxide 7 000 000 151.0 mg  2250 g  45.0 (Polyox WSR 303, DowChemicals) Hypromellose (Metholose 90 33.6 mg 500 g 10.0 SH 100 000 cP,ShinEtsu) Eudragit E Granulate (Röhm) 16.8 mg 250 g 5.0 PEG 6000 33.6 mg500 g 10.0 □-tocopherol  0.1 mg  5 g 0.1 Aerosil (highly disperse SiO₂) 0.1 mg  5 g 0.1

A homogeneous mixture of 50 g of the polyethylene oxide, 5 g of□-tocopherol and Aerosil was prepared in a mortar. Said homogeneousmixture was mixed with the further components in a free-fall mixer for15 minutes. Subsequently, the mixtures was extruded by means of aplanetary-gear extruder, type BCG 10, LBB Bohle (Ennigerloh). 4 spindleswere used. The die diameter was 8 mm. The dosing of the powder wasperformed gravimetrically, 10 kg per hour. The following parameters wereadjusted for extrusion: rotation speed: 50 UpM; cover temperature: 100°C.; temperature of the central spindle: 100° C.; temperature of the jetheating: 120° C. After preparation the extrudates were allowed to cooldown to room temperature. Thereafter, they were cut into slides havingthe desired tablet weight. Moulding of the tablets was performed bymeans of an excenter press, type EKO, Korsch. Circular punches having adiameter of 10 mm and a radius of curvature of 8 mm were used astabletting tool.

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. This could not be achieved with the assistanceof a pestle and mortar either.

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus in accordance with Pharm. Eur.The temperature of the release medium (600 ml) was 37° C. and therotational speed 75 rpm. The phosphate buffer, pH 6.8, described in DSPserved as the release medium. The quantity of active ingredient presentin the solvent at the particular time of testing was determined byspectrophotometry. Time amount released  30 min 17% 240 min 65% 480 min93% 720 min 99%

EXAMPLE 17

Tablets having the following composition were produced as described inExample 16: per complete content components tablet batch [%] tramadolHCl 100.0 mg  1490 g  29.8 polyethylene oxide 7 000 000 151.0 mg  2250g  45.0 (Polyox WSR 303, Dow Chemicals) Hypromellose (Metholose 90 33.6mg 500 g 10.0 SH 100 000 cP, ShinEtsu) Stamylan LD 1965 (SABIC ® 16.8 mg250 g 5.0 LDPE 1965T) (Sabic Europetrochemicals) PEG 6000 33.6 mg 500 g10.0 □-tocopherol  0.1 mg  5 g 0.1 Aerosil (highly disperse SiO₂)  0.1mg  5 g 0.1

The resistance to crushing of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. Nor could this be achieved with the assistanceof a pestle and mortar.

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus in accordance with Pharm. Eur.(paddle with sinker). The temperature of the release medium was 37° C.and the rotational speed of the stirrer 75 min⁻¹. 600 ml of artificialintestinal fluid pH 6.8 were used as release medium. The quantity ofactive ingredient released in each case into the dissolution medium atany one time was determined by spectrophotometry. time amount released 30 min 17% 240 min 62% 480 min 85% 720 min 94%

1. A dosage form comprising a physiologically effective amount of aphysiologically active substance (A), a synthetic, semi-synthetic ornatural polymer (C), optionally one or more physiologically acceptableauxiliary substances (B) and optionally a synthetic, semi-synthetic ornatural wax (D), wherein the dosage form exhibits a resistance tocrushing of at least 400 N and wherein under physiological conditionsthe release of the physiologically active substance (A) from the dosageform is at least partially delayed.
 2. The dosage form according toclaim 1, which exhibits a resistance to crushing of at least 500 N. 3.The dosage form according to claim 1, which is in the form of a tablet.4. The dosage form according to claim 1 which is in multiparticulateform, the individual particles exhibiting a resistance to crushing of atleast 400 N.
 5. The dosage form according to claim 4, wherein theparticles are pressed into tablets or packaged in capsules.
 6. Thedosage form according to claim 1, wherein polymer (C) is selected fromthe group consisting of polyalkylene oxide, polyethylene, polypropylene,polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, thecopolymers thereof and mixtures thereof.
 7. The dosage form according toclaim 1, wherein polymer (C) is an polyalkylene oxide selected from thegroup consisting of polymethylene oxide, polyethylene oxide,polypropylene oxide, the copolymers thereof, the block-copolymersthereof, and the mixtures of any of the foregoing.
 8. The dosage formaccording to claim 6, wherein polymer (C) has a molecular weight of atleast 0.5 million according to rheological measurements.
 9. The dosageform according to claim 1, which comprises a tubular domain (82) and acore (83) located therein, wherein the tubular domain (82) is connectedwith the core (83) in a seamless manner and the material forming thetubular domain (82) and the material forming the core (83) havesubstantially the same chemical composition but different morphology.10. The dosage form according to claim 9, wherein the material formingthe tubular domain (82) and the material forming the core (83) havedifferent optical properties.
 11. The dosage form according to claim 9,wherein the thickness of the tubular domain (82) is within the range of0.1 to 4 mm.
 12. The dosage form according to claim 1, wherein uponstorage for at least 12 hour at a temperature of 20° C. below themelting range of the mixture of components (A), (C), optionally (B) andoptionally (D) the volume of the dosage form increases by not more than20%.
 13. The dosage form according to claim 1, wherein wax (D) is atleast one synthetic, semi-synthetic or natural wax with a softeningpoint of at least 50° C.
 14. The dosage form according to claim 13,wherein wax (D) is carnauba wax or beeswax.
 15. The dosage formaccording to claim 1, wherein substance (A) is present in adelayed-release matrix.
 16. The dosage form according to claim 15,wherein the delayed-release matrix comprises polymer (C) and/or theoptionally present wax (D).
 17. The dosage form according to claim 1,wherein after 5 hours under physiological conditions it has released notmore than 99% of substance (A).
 18. The dosage form according to claim1, wherein substance (A) is a nutritional supplement or a pharmaceuticalsubstance.
 19. The dosage form according to claim 18, wherein substance(A) is selected from the group consisting of agents for the treatmentand prevention of diseases of the alimentary system and metabolism;agents for the treatment and prevention of diseases of the blood and theblood forming organs; agents for the treatment and prevention ofdiseases of the cardiovascular system; dermatologicals; agents for thetreatment and prevention of diseases of the genitourinary system and sexhormones; systemic hormone preparations excluding sex hormones andinsulins; antiinfectives for systemic use; antineoplastic andimmunomodulating agents; agents for the treatment and prevention ofdiseases of the musculo-skeletal system; agents for the treatment andprevention of diseases of the nervous system; antiparasitic products,insecticides and repellents; agents for the treatment and prevention ofdiseases of the respiratory system; agents for the treatment andprevention of diseases of the sensory organs; general diet products andtherapeutic radiopharmaceuticals.
 20. A process for the production of adosage form according to claim 1 comprising the following steps: (a)mixing of component (A), (C), optionally (B) and optionally (D); (b)optionally preforming the mixture obtained from step (a), preferably byapplying heat and/or force to the mixture obtained from step (a), thequantity of heat supplied preferably not being sufficient to heatcomponent (C) up to its softening point; (c) hardening the mixture byapplying heat and force, where the heat is supplied during and/or beforethe application of force and the quantity of heat supplied is sufficientto heat component (C) at least up to its softening point; (d) optionallysingulating the hardened mixture; (e) optionally shaping the dosageform; and (f) optionally providing a film coating.
 21. The processaccording to claim 20, wherein step (c) is performed by means of atwin-screw-extruder or a planetary-gear extruder.
 22. The processaccording to claim 21, wherein step (e) is performed in the plasticizedstate of the mixture of components (A), (C), optionally (B) andoptionally (D).
 23. The process according to claim 20, wherein step (c)is performed by the effect of ultrasound and force.
 24. The product ofthe process of claim
 20. 25. The product of the process of claim
 21. 26.The product of the process of claim
 22. 27. The product of the processof claim
 23. 28. A method of preventing the misuse or abuse of a dosageform containing a physiologically active substance (A), due tocomminution of the dosage form by mechanical action comprisingadministering the active substance to a patient in need thereof in adosage form in accordance with claim
 1. 29. The use according to claim25 or the method according to claim 26, wherein the mechanical action isselected from the group consisting of chewing, grinding in a mortar,pounding, and using apparatuses for pulverising conventional dosageforms.
 30. A method for the prophylaxis and/or the treatment of adisorder treatable by the administration of a therapeutically effectiveamount of an agent capable of treating such disorder comprisingadministering a dosage form according to claim 1 to prevent theunintentional disruption of the controlled release mechanism of thephysiologically active substance (A) which can result from crushing orchewing the dosage form.
 31. A method of preventing an accidentaloverdose of a physiologically active substance comprising administeringthe active substance to a patient in need thereof in a dosage form inaccordance with claim
 1. 32. A method of preventing the misuse or abuseof a physiologically active substance comprising administering theactive substance to a patient in need thereof in a dosage form inaccordance with claim
 1. 33. A method of preventing the disruption of acontrolled release mechanism in a dosage form comprising aphysiologically active substance intended for controlled release of suchactive substance comprising administering the active substance in adosage form according to claim 1.